Lack of Siglec-7 expression identifies a dysfunctional natural killer cell subset associated with liver inflammation and fibrosis in chronic HCV infection

Varchetta, Stefania; Mele, Dalila; Lombardi, Andrea; Oliviero, Barbara; Mantovani, Stefania; Tinelli, Carmine; Spreafico, M.; Prati, Daniele; Ludovisi, Serena; Ferraioli, Giovanna; Fı̀lice, Carlo; Aghemo, Alessio; Lampertico, Pietro; Facchetti, F.; Bernuzzi, Francesca; Invernizzi, Pietro; Mondelli, Mario U.

doi:10.1136/gutjnl-2015-310327

Cited by 46 publications

(48 citation statements)

References 38 publications

(37 reference statements)

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“…In Figure 2, we show similar correlation coefficients between Siglec-7 and these serologies as Varchetta et al did, highlighting the reproducibility of the Siglec-7 assay in a distinct population. (14) We are able to build on these findings in our prospective study by extending that serum Siglec-7 levels were associated with increased mortality in an independent cohort. This helps confirm an important connection between liver inflammation, immune dysregulation, and clinical outcomes in cirrhosis.…”

Section: Discussionmentioning

confidence: 67%

“…highlighted the potential pathobiologic connection between Siglec-7, immune dysregulation, and severe liver disease. (14) In a large cross-sectional study, these investigators demonstrated an increase in soluble serum Siglec-7 in a population with hepatitis C infection, and a correlation between Siglec-7 and levels of other clinical biomarkers of liver disease. This suggests that higher soluble Siglec-7 may denote a high inflammatory state in the liver and may be mechanistically important in this disease process.…”

Section: Discussionmentioning

confidence: 99%

“…(44, 45) The absence of Siglec-7 expression on natural killer cells and the increase in soluble serum levels suggest that these immune cells are dysfunctional in advanced liver disease. (14) Future studies may be able to better elicit whether modulation of the Siglec-7 pathway is a viable target of therapy. There are monoclonal antibodies that target Siglec-2 and Siglec-3 receptors and are treatments for hematologic malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…(21–30) In addition, a recent publication showed that in chronic hepatitis C infection, known markers of liver inflammation and advanced fibrosis correlated with increasing soluble serum Siglec-7 levels, but no study has yet investigated the association of Siglec-7 and concrete clinical outcomes in liver disease, such as survival. (14)…”

Section: Introductionmentioning

confidence: 99%

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Siglec-7 as a Novel Biomarker to Predict Mortality in Decompensated Cirrhosis and Acute Kidney Injury

et al. 2016

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Background Patients with decompensated cirrhosis have high morbidity and are commonly hospitalized with acute kidney injury. Aims We examined serum levels of Siglec-7, a transmembrane receptor that regulates immune activity, as a biomarker for mortality in patients with cirrhosis and acute kidney injury. Methods Serum Siglec-7 was measured in hospitalized patients with cirrhosis and acute kidney injury, as well as in reference groups with acute liver injury/acute kidney injury, cirrhosis without acute kidney injury, and sepsis without liver disease. Clinical characteristics and subsequent outcomes were examined using univariate and multivariable analyses according to initial Siglec-7 levels. Primary outcome was death by 90 days. Results One hundred twenty-eight subjects were included, 92 of which had cirrhosis and acute kidney injury and were used in the primary analysis. Average Model for End Stage Liver Disease (MELD) score was 24 [95% CI 23, 26] and serum creatinine was 2.5 [2.2, 2.8] mg/dL at the time Siglec-7 was measured. After adjusting for age and MELD score, high serum Siglec-7 level predicted mortality with a hazard ratio of 1.96 [1.04, 3.69; p = 0.04]. There was no difference in Siglec-7 levels by etiology of AKI (p = 0.24). Addition of serum Siglec-7 to MELD score improved discrimination for 90-day mortality (category-free net reclassification index = 0.38 (p = 0.04); integrated discrimination increment = 0.043 (p = 0.04)). Conclusion Serum Siglec-7 was associated with increased mortality among hospitalized patients with cirrhosis and acute kidney injury. Addition of Siglec-7 to MELD score may increase discrimination to predict 90-day mortality.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Siglec-7 as a Novel Biomarker to Predict Mortality in Decompensated Cirrhosis and Acute Kidney Injury

et al. 2016

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“…Among circulating immune cells constitutively expressing this C-lectin-type molecule (i.e., NK cells and monocytes) (5), the main source of sSiglec-7 seems to be NK cells because a subset of Siglec-7 neg monocytes has never been reported during the course of HIV-1 infection (52). Similarly, it has been recently shown that also the stimulation in vitro of NK cells with HCV induces both a significant release of sSiglec-7 in culture supernatant and a decrease of Siglec-7 expression from NK cell surface (77). Further investigations are required to identify the cellular and molecular mechanisms that certain viruses employ to induce a shedding of this C lectin-type receptor selectively on NK cells during the acute phases of the infection.…”

Section: Kinetics Of Siglecs During the Course Of Hiv-1 Infectionmentioning

confidence: 97%

Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates

et al. 2017

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A better understanding of the mechanisms employed by HIV-1 to escape immune responses still represents one of the major tasks required for the development of novel therapeutic approaches targeting a disease still lacking a definitive cure. Host innate immune responses against HIV-1 are key in the early phases of the infection as they could prevent the development and the establishment of two hallmarks of the infection: chronic inflammation and viral reservoirs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to a family of transmembrane proteins able to dampen host immune responses and set appropriate immune activation thresholds upon ligation with their natural ligands, the sialylated carbohydrates. This immune-modulatory function is also targeted by many pathogens that have evolved to express sialic acids on their surface in order to escape host immune responses. HIV-1 envelope glycoprotein 120 (gp120) is extensively covered by carbohydrates playing active roles in life cycle of the virus. Indeed, besides forming a protecting shield from antibody recognition, this coat of N-linked glycans interferes with the folding of viral glycoproteins and enhances virus infectivity. In particular, the sialic acid residues present on gp120 can bind Siglec-7 on natural killer and monocytes/macrophages and Siglec-1 on monocytes/macrophages and dendritic cells. The interactions between these two members of the Siglec family and the sialylated glycans present on HIV-1 envelope either induce or increase HIV-1 entry in conventional and unconventional target cells, thus contributing to viral dissemination and disease progression. In this review, we address the impact of Siglecs in the pathogenesis of HIV-1 infection and discuss how they could be employed as clinic and therapeutic targets.

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Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis

Ferrari

Mondelli

2009

The Liver

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Lack of Siglec-7 expression identifies a dysfunctional natural killer cell subset associated with liver inflammation and fibrosis in chronic HCV infection

Abstract: These findings identify Siglec-7 NK cells as a dysfunctional subpopulation associated with severe liver disease in chronic HCV infection.

Cited by 46 publications

References 38 publications

Siglec-7 as a Novel Biomarker to Predict Mortality in Decompensated Cirrhosis and Acute Kidney Injury

Siglec-7 as a Novel Biomarker to Predict Mortality in Decompensated Cirrhosis and Acute Kidney Injury

Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates

Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis

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