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Serum levels of the interferon‐γ‐inducible α chemokine CXCL10 in patients with active Graves' disease, and modulation by methimazole therapy and thyroidectomy

The interferon‐γ‐inducible chemokine CXCL10 is highly expressed in infiltrating inflammatory cells, and in thyrocytes in patients with Graves disease. The aim of this study was to measure serum levels of CXCL10 in relation to thyroid function and treatment.

Hepatitis C virus infection and type 1 and type 2 diabetes mellitus

Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.

CXCL10 and CCL2 serum levels in patients with mixed cryoglobulinaemia and hepatitis C

BACKGROUNDnNo study evaluates serum levels of CXCL10 and CCL2 chemokines in patients with hepatitis C associated mixed cryoglobulinaemia.nnnAIMSnTo measure circulating CXCL10 and CCL2 in cryoglobulinaemic patients.nnnPATIENTS AND METHODSnSerum CXCL10 and CCL2 were assayed in 70 consecutive cryoglobulinaemic patients, and in 2 control groups (1:1, gender- and age-matched) of healthy (controls), or of chronic hepatitis C subjects without cryoglobulinaemia.nnnRESULTSnCryoglobulinaemic patients showed higher CXCL10 serum levels than controls (p<0.0001), or hepatitis C patients (p=0.001) (389 +/- 141, 91 +/- 51, 311 +/- 142 pg/ml, respectively). By defining a high CXCL10 as a value at least 2 S.D. above the mean value of the control group (>193 pg/ml), 79% of cryoglobulinaemic patients, 5% of the controls and 69% of hepatitis C patients had high CXCL10 (p<0.0001). CXCL10 levels were (p<0.01) increased in cryoglobulinaemic patients with active vasculitis, with respect to those without (445+/-108, 339 +/- 161 pg/ml, respectively). Cryoglobulinaemic patients showed significantly higher CCL2 serum level than controls (p<0.01), but not than hepatitis C patients (541 +/- 493, 387 +/- 173 and 451 +/- 281 pg/ml, respectively).nnnCONCLUSIONnOur study first demonstrates high serum levels of CXCL10 and CCL2 chemokines in cryoglobulinaemic patients. Circulating CXCL10 is higher overall in cryoglobulinaemic patients with active vasculitis, suggesting a prevalence of the Th1 immune response in this phase.

IP-10 in autoimmune thyroiditis.

The interferon-γ-inducible protein 10 (IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. IP-10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). IP-10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of IP-10 by (CD)4+, CD8+, and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, IP-10 is secreted by thyrocytes. Determination of high level of IP-10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating IP-10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, IP-10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, which is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons, it has been postulated that IP-10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in AT.

High levels of circulating N‐terminal pro‐brain natriuretic peptide in patients with hepatitis C

Summary.u2002 Many patients chronically infected by hepatitis C virus (HCV) experience symptoms like fatigue, dyspnea and reduced physical activity. However, in many patients, these symptoms are not proportional to the liver involvement and could resemble symptoms of chronic heart failure. To our knowledge, no study evaluated serum levels of N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) in a large series of patients with HCV chronic infection (HCV+). Serum NT‐proBNP was assayed in 50 patients HCV+ and in 50 sex‐ and age‐matched controls. HCV+ patients showed significantly higher mean NT‐proBNP level than controls (P = 0.001). By defining high NT‐proBNP level as a value higher than 125 pg/mL (the single cut‐off point for patient under 75 years of age), 34% HCV+ and 6% controls had high NT‐proBNP (Fisher exact test; P < 0.001). With a cut‐off point of 300 pg/mL (used to rule out chronic heart failure in patients under 75 years of age) 10% HCV+ and 0 controls had high NT‐proBNP (Fisher exact test; P = 0.056). With a cut‐off point of 900 pg/mL (used for ruling in chronic heart failure in patients with age 50–75) 8% HCV+ patients and 0 controls had high NT‐proBNP (Fisher exact test; P = 0.12). The study demonstrates high levels of circulating NT‐proBNP in HCV+ patients compared to healthy controls. The increase of NT‐proBNP may indicate the presence of a sub‐clinical cardiac dysfunction. Further prospective studies quantifying these symptoms in correlation with echocardiography are needed to confirm this association.

Peroxisome proliferator-activated receptor γ agonists reduce cell proliferation and viability and increase apoptosis in systemic sclerosis fibroblasts

Backgroundu2002 No study has evaluated the effect of the peroxisome proliferator‐activated receptor γ (PPARγ) agonists on cell viability, proliferation and apoptosis in cultured systemic sclerosis (SSc) fibroblasts.

Mixed cryoglobulinemia and thyroid autoimmune disorders

In patients with hepatitis C virus-associated mixed cryoglobulinemia (MC+HCV) the following thyroid disorders are significantly more frequent than in HCV not infected controls: 1) high levels of serum anti-thyroperoxidase autoantibody (AbTPO), 2) high levels of serum AbTPO and/or anti-thyroglobulin (AbTg) autoantibody; 3) humoral and ultrasonographical signs of thyroid autoimmunity (35%); 4) prevalence of subclinical hypothyroidism (11%). Also, the prevalence of papillary thyroid cancer has been found higher in MC+HCV patients than in controls, in particular in patients with autoimmune thyroiditis. These results suggest a careful monitoring of thyroid function in these patients.

High circulating chemokines (C-X-C motif) ligand 9, and (C-X-C motif) ligand 11, in hepatitis C-associated cryoglobulinemia.

(C-X-C motif) ligand 9 and (C-X-C motif) ligand 11 (CXCL9 and CXCL11), are potent chemoattractants for activated T cells, and play an important role in T helper 1 (Th) 1 cell recruitment in chronic hepatitis C. No study has evaluated CXCL9, together with CXCL11, circulating levels in patients with mixed cryoglobulinemia and hepatitis C (MC+HCV-p). The aim of the present study therefore was to measure serum CXCL9, and CXCL11 levels, in MC+HCV-p, and to relate the findings to the clinical phenotype. Serum CXCL9 and CXCL11 were measured in 71 MC+HCV-p and in matched controls. MC+HCV-p showed significantly higher mean CXCL9 and CXCL11 levels than controls (P < 0.001, for both), in particular, in 32 patients with active vasculitis (P < 0.001). By defining high CXCL9 or CXCL11 level as a value of at least 2 SD above the mean value of the control group (> 100 pg/mL): 89% MC+HCV-p and 5% controls had high CXCL9 (P < 0.0001, chi-square); 90% MC+HCV-p and 6% controls had high CXCL11 (P < 0.0001, chi-square). In a multiple linear regression model of CXCL9 vs age, ALT, CXCL11, only CXCL11 was significantly (r = 0.452, P < 0.0001) and independently related to CXCL9. Our study demonstrates in MC+HCV-p vs controls: (i) high serum CXCL9, and CXCL11, significantly associated with the presence of active vasculitis; (ii) a strong relationship between circulating CXCL9 and CXCL11. Future studies on a larger cohort of patients are needed to evaluate the relevance of serum CXCL9 and CXCL11 determination as clinico-prognostic marker of MC+HCV.

Systemic Sclerosis Fibroblasts Show Specific Alterations of Interferon-γ and Tumor Necrosis Factor-α-induced Modulation of Interleukin 6 and Chemokine Ligand 2

Objective. We evaluated the effect of interferon-γ (IFN-γ) and/or tumor necrosis factor-α (TNF-α) on the secretion of prototype proinflammatory cytokine interleukin 6 (IL-6), compared to T-helper 1 [Th1; chemokine (C-X-C motif) ligand 10 (CXCL10)] or Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines, in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease. Methods. Fibroblast cultures from 5 SSc patients (disease duration < 2 yrs) and 5 healthy controls were evaluated for the production of IL-6, CXCL10, and CCL2 at the basal level and after stimulation with IFN-γ and/or TNF-α. Results. SSc fibroblasts basally produced higher levels of IL-6 than controls, while no difference was observed about CCL2 and CXCL10. TNF-α was able to dose-dependently induce IL-6 and CCL2 secretion in SSc, but not in control fibroblasts. By stimulation with increasing doses of IFN-γ, SSc fibroblasts were induced to secrete CCL2 and CXCL10, while no effect was observed on IL-6. The combination of IFN-γ and TNF-α induced a strong secretion of IL-6 and CCL2 in SSc fibroblasts but not in controls. In contrast, the synergistic effect of IFN-γ and TNF-α on CXCL10 secretion was similar in SSc fibroblasts and in controls. Conclusion. SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, CXCL10, and CCL2 under the influence of IFN-γ and/or TNF-α. SSc fibroblasts are more active than controls in the secretion of IL-6 at baseline, and in the production of IL-6 and CCL2 under the combined IFN-γ/TNF-α stimulation.

IFN-γ and TNF-α induce a different modulation of interleukin-6 in systemic sclerosis fibroblasts compared to healthy controls

Background: To our knowledge, no previous study has evaluated the effect of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, or their combination on the prototype proinflammatory cytokine interleukin (IL)-6 in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease. Methods: Fibroblast cultures from five SSc patients (disease duration < 2 years) and five healthy controls were evaluated for the basal production of IL-6, and after stimulation with TNF-α or IFN-γ, alone or combined. Results: The fibroblasts from SSc patients produced higher levels of IL-6 in basal condition than controls [617 ± 173 vs. 213 ± 123 pg/mL; analysis of variance (ANOVA), p < 0.001]. TNF-α was able to dose-dependently induce IL-6 in SSc (609 ± 184, 723 ± 243, 1079 ± 297, 1436 ± 326 pg/mL, with TNF-α 0, 1, 5, 10 ng/mL, respectively) but not in control fibroblasts, whereas IFN-γ was unable to induce IL-6. Furthermore, the combination of IFN-γ and TNF-α induced a stronger secretion of IL-6 in SSc fibroblasts (ANOVA, p < 0.0001), without effect in controls. Conclusions: SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, under the influence of TNF-α and/or IFN-γ.