Abstract The cytoplasmic S100 proteins derived from cells of myeloid origin are promising new markers of (auto-)inflammation. S100A8/A9 and S100A12 are released from monocytes and granulocytes during ...activation of the innate immune system. Tissue and serum concentrations correlate to disease activity, both during local and systemic inflammation. In autoinflammatory diseases such as Familial Mediterranean Fever (FMF) and Systemic onset Juvenile Idiopathic Arthritis (SJIA), a dysregulation of alternative secretory pathways may be involved in pathogenesis and lead to hypersecretion of S100 proteins. Since autoinflammatory diseases can be difficult to diagnose, phagocyte-derived S100 proteins are valid tools in the diagnosis of autoinflammatory diseases. In addition, they may help achieve a better understanding of the pathophysiology of autoinflammatory disorders including SJIA and FMF, and even provide novel therapeutic targets in the future.
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes ...familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.
•IL-18 distinguishes susceptibility to MAS amongst hyperferritinemic and autoinflammatory diseases.•Excess IL-18 in NLRC4 gain-of-function mice derives from intestinal epithelia, and free IL-18 promotes experimental MAS.
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The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also ...activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin-induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.
Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid ...origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term "S100/calgranulins." Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.
Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever ...syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.
Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.
The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).
Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Crohn's disease (CD) and ulcerative colitis (UC) have a chronic-remittent course. Optimal management of inflammatory bowel diseases (IBD) relies on early intervention, treat-to-target strategies and ...a tight disease control. However, it is challenging to assess the risk of relapses in individual patients. We investigated blood-based biomarkers for the confirmation of disease remission in patients with IBD. We retrospectively analyzed samples of 40 IBD patients (30 UC, 10 CD) enrolled in a tight-control follow-up study. Half of the patients had a flare during follow up. Serum was analyzed for S100A12 as well as S100A8/A9 and for 50 further biomarkers in a bead-based multiplex assay. The concentrations of 9 cytokines/chemokines and S100A8/A9 significantly differed in IBD patients with unstable remission (before flares) when compared to IBD patients with stable remission. Although the number of patients was small, ROC curve analyses revealed a number of biomarkers (IL-1β, IL-1RA, IL-8, IL13, IL-15, IL-21, IL-25, IFN-β, CXCL9, CXCL10, CXCL11, Galectin-1, G-CSF and S100A8/A9) that were elevated in patients with later occurring relapses. While earlier studies on peripheral biomarkers in IBD are limited to only few analytes, our study using a broad screening approach identified serum biomarkers with the potential to indicate unstable disease control in IBD, which may help to steer individual therapies to maintain remission.
Abstract
The interactions of fibroblast-like synoviocyte (FLS)-derived pro-inflammatory cytokines/chemokines and immune cells support the recruitment and activation of inflammatory cells in RA. Here, ...we show for the first time that the classical myokine myostatin (GDF-8) is involved in the recruitment of Th17 cells to inflammatory sites thereby regulating joint inflammation in a mouse model of TNFalpha-mediated chronic arthritis. Mechanistically, myostatin-deficiency leads to decreased levels of the chemokine CCL20 which is associated with less infiltration of Th17 cells into the inflamed joints. In vitro, myostatin alone or in combination with IL-17A enhances the secretion of CCL20 by FLS whereas myostatin-deficiency reduces CCL20 secretion, associated with an altered transmigration of Th17 cells. Thus, the communication between activated FLS and Th17 cells through myostatin and IL-17A may likely contribute to a vicious cycle of inflammation, accounting for the persistence of joint inflammation in chronic arthritis. Blockade of the CCL20–CCR6 axis by inhibition of myostatin may, therefore, be a promising treatment option for chronic inflammatory diseases such as arthritis.
Chronic inflammation is a complex process that promotes carcinogenesis and tumor progression; however, the mechanisms by which specific inflammatory mediators contribute to tumor growth remain ...unclear. We and others recently demonstrated that the inflammatory mediators IL-1beta, IL-6, and PGE(2) induce accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing individuals. MDSC impair tumor immunity and thereby facilitate carcinogenesis and tumor progression by inhibiting T and NK cell activation, and by polarizing immunity toward a tumor-promoting type 2 phenotype. We now show that this population of immature myeloid cells induced by a given tumor share a common phenotype regardless of their in vivo location (bone marrow, spleen, blood, or tumor site), and that Gr1(high)CD11b(high)F4/80(-)CD80(+)IL4Ralpha(+/-)Arginase(+) MDSC are induced by the proinflammatory proteins S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration. MDSC also synthesize and secrete S100A8/A9 proteins that accumulate in the serum of tumor-bearing mice, and in vivo blocking of S100A8/A9 binding to MDSC using an anti-carboxylated glycan Ab reduces MDSC levels in blood and secondary lymphoid organs in mice with metastatic disease. Therefore, the S100 family of inflammatory mediators serves as an autocrine feedback loop that sustains accumulation of MDSC. Since S100A8/A9 activation of MDSC is through the NF-kappaB signaling pathway, drugs that target this pathway may reduce MDSC levels and be useful therapeutic agents in conjunction with active immunotherapy in cancer patients.
Objective
Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients ...still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat‐to‐target approach using recombinant interleukin‐1 receptor antagonist (rIL‐1Ra; anakinra) as first‐line monotherapy to achieve early inactive disease and prevent damage.
Methods
In this single‐center, prospective study, patients with new‐onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL‐1Ra monotherapy according to a treat‐to‐target strategy. Patients with an incomplete response to 2 mg/kg rIL‐1Ra subsequently received 4 mg/kg rIL‐1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL‐1Ra was tapered after 3 months and subsequently stopped.
Results
Forty‐two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL‐1Ra were highly associated with inactive disease at 1 year. After 5 years of follow‐up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL‐1Ra was equally effective in systemic JIA patients without arthritis at disease onset.
Conclusion
Treatment to target, starting with first‐line, short‐course monotherapy with rIL‐1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease‐ and glucocorticoid‐related damage in systemic JIA.
Innate immunity achieves our primary host defense by recognizing invading microorganisms through pathogen-associated molecular patterns (PAMPs) and by reacting to tissue damage signals called ...damage-associated molecular patterns (DAMPs). DAMP molecules, including high mobility group box 1 protein (HMGB-1), heat-shock proteins (HSPs), uric acid, altered matrix proteins, and S100 proteins, represent important danger signals that mediate inflammatory responses through the receptor for advanced glycation end-products (RAGE, also known as AGER) and Toll-like receptors, after release from activated or necrotic cells. The terms 'alarmins' and 'endokines' have also been proposed for DAMP molecules. A prototypic DAMP molecule, the nuclear protein HMGB-1, is either passively released by necrotic cells or actively secreted with delay by activated cells. S100A8, S100A9, and S100A12 are calcium-binding proteins expressed in the cytoplasm of phagocytes. They are rapidly secreted by activated monocytes or neutrophils, which are abundant in inflamed synovial tissue. HSPs are involved in the crosstalk between innate and adaptive immune systems, and primarily mediate immune regulatory functions. Multiple positive feedback loops between DAMPs and PAMPs and their overlapping receptors temporally and spatially drive these processes and may represent the molecular basis for the observation that infections, as well as nonspecific stress factors, can trigger flares in rheumatic diseases.
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