Differential serum cytokine profile in patients with systemic lupus erythematosus and posterior reversible encephalopathy syndrome

Systemic lupus erythematosus (SLE) patients are susceptible to the development of posterior reversible encephalopathy syndrome (PRES). The main theory concerning the physiopathology of PRES suggests that there is brain–blood barrier damage, which is associated with endothelial dysfunction, and characterized by vasogenic oedema. However, current evidence regarding its physiopathogenic mechanisms is quite scant. The aim of this study was to analyse the expression of different serum cytokines, as well as vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L), in patients with PRES/systemic lupus erythematosus (SLE) and to compare them with levels in SLE patients without PRES and in healthy controls. We performed a transversal study in a tertiary care centre in México City. We included 32 subjects (healthy controls, n = 6; remission SLE, n = 6; active SLE, n = 6 and PRES/SLE patients, n = 14). PRES was defined as reversible neurological manifestations (seizures, visual abnormalities, acute confusional state), associated with compatible changes by magnetic resonance imaging (MRI). Serum samples were obtained during the first 36 h after the PRES episode and were analysed by cytometric bead array, Luminex multiplex assay or enzyme‐linked immunosorbent assay (ELISA). Interleukin (IL)‐6 and IL‐10 levels were significantly higher in PRES/SLE patients (P = 0·013 and 0·025, respectively) when compared to the other groups. Furthermore, IL‐6 and IL‐10 levels displayed a positive correlation (r = 0·686, P = 0·007). There were no differences among groups regarding other cytokines, sCD40L or VEGF levels. A differential serum cytokine profile was found in PRES/SLE patients, with increased IL‐6 and IL‐10 levels. Our findings, which are similar to those described in other neurological manifestations of SLE, support the fact that PRES should be considered among the SLE‐associated neuropsychiatric syndromes.     

Proximal interleukin-10 gene polymorphisms in Italian patients with systemic sclerosis

Interleukin-10 (IL-10) can favour the development of fibrosis by promoting a relative shift towards T helper 2 responses. Three single base pair substitutions in the 5' flanking region of the IL-10 gene (G/A -1082, C/T -819 and C/A -592) influence the amount of IL-10 secreted in cell cultures: the GCC haplotype is associated with an increased production, while the ACC and the ATA haplotypes are associated with intermediate and decreased production. Accordingly, three phenotypes have been individuated: high producers (GCC+/GCC+), medium producers (GCC+/GCC-) and low producers (GCC-/GCC-). We hypothesised that IL-10 haplotypes and genotypes are differently expressed in patients with systemic sclerosis (SSc) with the limited cutaneous SSc (lcSSc) subset or the diffuse cutaneous SSc (dcSSc) subset. One hundred and sixty-one unrelated Italian patients with SSc and 94 controls have been included. Their DNA was extracted and stored before being analysed by polymerase chain reaction with sequence-specific primers. The GCC haplotype is overrepresented in patients with SSc; subjects with dcSSc were the primary contributors to these results (dcSSc: 52.2% vs controls: 37.2%; chi2= 8.519, 2 d.f., corrected P= 0.04). In Scl70-positive patients, the GCC haplotype increased the likelihood of presenting the dcSSc subset [chi2= 12.56, P < 0.0005; odds ratio (OR) = 3.89, 95% confidence interval (CI(95)) = 1.69-9.08]; these results were confirmed at the phenotypic level (chi2= 11.67, 2 d.f., P= 0.003). In Scl70-positive patients, the high-producing phenotype was associated with poor survival, independently from disease subset and gender (hazard ratio = 9.9, CI(95)= 1.6-61.27, P < 0.05). The IL-10 haplotype and genotype associated with high IL-10 production may alter the susceptibility to SSc and/or its expression, increasing the prognostic value of other well-known markers of disease severity.     

Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis

To study the immunosuppressive and anti-inflammatory effects of combined leflunomide and methotrexate (MTX) therapy on chemokine expression in patients with rheumatoid arthritis (RA), nine patients were enrolled for the combination therapy for 24 weeks. These patients have been on treatment with MTX 15 mg/week for not less than 3 months before entry to the study. A loading dose of l00 mg/day of leflunomide was given for 3 days, followed by 10 mg/day for the rest of the study period. Plasma concentrations of monocyte chemotactic protein-1 (MCP-1), thymus- and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) were assayed before and after combination treatment by ELISA. Gene expression of inflammatory cytokines and chemokines of peripheral blood mononuclear cells was analysed by cDNA expression array. Plasma MCP-1, TARC and MDC concentrations were significantly lower in patients after combination treatment [median (interquartile range) before versus after treatment: MCP-1 of 118.0 (64.0-515.2) versus 3.2 (0.0-22.8) pg/ml, P < 0.01; TARC of 126.1 (27.2-197.4) versus 0.0 (0.0-52.5) pg/ml, P < 0.05; MDC of 503.3 (446.2-600.9) versus 366.8 (337.4-393.4) pg/ml, P < 0.05]. Positive correlations among reductions in plasma chemokines and clinical outcome measures were also found. Expression of chemokine genes including MDC and TARC was suppressed after combination treatment [% suppression of 38.7 (54.3-13.0) and 53.7 (55.9-28.4), respectively]. Combination therapy with leflunomide and MTX exhibits anti-inflammatory activity in the suppression of chemokine expression and subsequent recruitment of inflammatory cells into the inflammatory sites in RA.     

Decreased levels of autoantibody against histone deacetylase 3 in patients with systemic sclerosis

Systemic sclerosis (SSc) is characterized by immunological abnormalities, especially the production of autoantibodies against various cellular components. Treatment with histone deacetylase (HDAC) inhibitors prevents collagen accumulation in a mouse SSc model. Additionally, autoantibody against HDAC-3 is produced in colon cancer patients, while HDAC-1 and HDAC-2 do not elicit autoantibody response. To determine the presence and levels of antibodies (Abs) against HDAC-3 in SSc. Anti-HDAC-3 Ab was examined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting using human recombinant HDAC-3. The HDAC-3 activity was evaluated by ELISA using the fluorimetric HDAC lysyl substrate that comprises an acetylated lysine side chain. Contrary to our hypothesis that autoimmune background in SSc induced the production of autoantibody against HDACs, IgG and IgM anti-HDAC-3 Ab levels in SSc patients were significantly lower than in normal controls (p < 0.0005 and 0.001, respectively). Furthermore, decreased levels of IgG anti-HDAC-3 Ab were specific to SSc, since IgG anti-HDAC-3 Ab levels in patients with dermatomyositis (DM) and those with systemic lupus erythematosus (SLE) were similar and slightly increased relative to normal controls, respectively. Immunoblotting analysis showed that anti-HDAC-3 Ab was detected in normal controls and patients with DM or SLE, while it was absent in SSc patients. The HDAC-3 activity was significantly inhibited by IgG isolated from sera of normal controls, whereas such inhibitory effect was not observed by IgG isolated from sera of SSc patients. These results indicate the lack of anti-HDAC-3 autoantibody in SSc patients, which is produced in healthy individuals as well as DM and SLE patients, suggesting that this autoantibody might function as protective Ab.     

Correlation of serum IL-13 and IL-5 levels with clinical response to Glatiramer acetate in patients with multiple sclerosis

Glatiramer acetate (GA) is effective in the treatment of Multiple Sclerosis (MS) presumably by the induction of an immunoregulatory T-cell response. We have previously shown that GA directly induces the Th2 cytokines IL-13 and IL-5 in T-cells in vitro. In the present study we compared the in vitro response to GA in healthy controls, untreated and GA-treated MS patients and tested whether the induction of IL-13 and IL-5 secretion is also detectable in the serum of 25 MS patients treated with GA. Patients were grouped into clinical responders and nonresponders in order to determine a possible correlation with the immunological response. As a result we found a significant increase of IL-13 in the serum of clinical GA-responders whereas IL-13 was not detectable in controls, untreated MS (P < 0.001) and nonresponders (P = 0.015). Similarly, GA-treatment increased serum levels of IL-5 (P = 0.001). The correlation of serum IL-5 and clinical response was also significant (P = 0.039), however, there was an overlap between the different groups. The selective induction of IL-13 and IL-5 but not IL-4 by GA treatment suggests that the specific biological functions of these cytokines might be important for the therapeutic mechanism of GA. Measurement of serum IL-13 and IL-5 levels is a simple and inexpensive tool for monitoring the response to GA in MS patients.     

Transforming growth factor-beta1 polymorphisms in Korean patients with systemic sclerosis

Transforming growth factor-beta1 (TGF-beta1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate the role of TGF-beta1 gene polymorphisms in SSc, we genotyped six biallelic polymorphic positions (position -988, -800, and -509; and codons 10, 25, and 263) in 61 Korean SSc patients and in 148 healthy controls, using polymerase chain reaction-sequence-specific primers. Genetic polymorphisms were found at position -509 and codon 10 in Koreans. The allele frequencies of C/T at position -509 were 0.59/0.41 in patients and 0.56/0.44 in controls. The allele frequencies of C/T at codon 10 were 0.40/0.60 in patients and 0.50/0.50 in controls. In conclusion, no skewed distribution of TGF-beta1 gene polymorphisms was found in Korean patients with SSc.     

Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis

Activating and inhibitory signal transducers, CD19 and CD22, have been substantially implicated both in human systemic sclerosis (SSc) and tight-skin mouse, a model for SSc. We previously showed that a single nucleotide polymorphism (SNP) in CD19 promoter region was significantly associated with increased CD19 expression level and with susceptibility to SSc. In the present study, we examined whether CD22 polymorphisms were associated with susceptibility to SSc. CD22 variations were genotyped in 126 Japanese patients with SSc [47 diffuse cutaneous SSc and 79 limited cutaneous SSc (lcSSc)] and 93 unrelated healthy controls. At the c.2304C > A SNP coding for a synonymous substitution in exon 13, A/A genotype was observed in six patients with SSc (4.8 %) but none in the controls (P=0.040). All six patients with A/A genotype belonged to the lcSSc subgroup (7.6%, P=0.008 vs controls). Surface expression level of CD22 tended to be lower in B cells from the patients with A/A genotype (n=5) as compared with C/A (n=7) or C/C (n=14) genotype (17% decrease, P=0.0032). Taken together with our previous observation on CD19 polymorphism, intrinsic difference in the expression level of CD19 and CD22 was suggested to play a causative role in a proportion of patients with lcSSc.     

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis

Systemic sclerosis (SSc) is characterized by multi-organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti-MMP-1 antibody is suggested to inhibit MMP-1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti-MMP-1 antibody alone. In this study, we examined the presence or levels of antibody to MMP-3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme-linked immunosorbent assay (ELISA) using human recombinant MMP-3 revealed that IgG anti-MMP-3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti-MMP-3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti-MMP-3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti-MMP-3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP-3 activity was inhibited by IgG anti-MMP-3 antibody. These results suggest that anti-MMP-3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP-3 activity and reducing the ECM turnover.     

Elevated serum L-selectin levels and decreased L-selectin expression on CD8(+) lymphocytes in systemic sclerosis

L-selectin is expressed on most circulating leucocytes and mediates leucocyte rolling on endothelium at sites of inflammation. Following rolling or activation of leucocytes, cell surface L-selectin is released as soluble L-selectin (sL-selectin). In the present study, we assessed serum levels of sL-selectin by ELISA and blood leucocyte L-selectin expression by flow cytometry in patients with systemic sclerosis (SSc). Serum levels of sL-selectin in patients with SSc (n = 51) were significantly higher than in normal controls (n = 30) while sL-selectin levels were similar for systemic lupus erythematosus patients (n = 20) and normal controls. Furthermore, SSc patients with elevated sL-selectin levels had inflammatory joint involvement, pitting scar/ulcers, and diffuse pigmentation more frequently than those with normal sL-selectin levels. The frequency of L-selectin(+) population among CD8(+) T cells was significantly decreased in SSc patients (n = 30) compared with normal controls (n = 20), while that among CD4(+) T cells, B cells, monocytes, and neutrophils was similar for SSc patients and normal controls. These suggest that elevated sL-selectin levels and decreased frequency of L-selectin+ CD8(+) T cells in SSc patients may be involved in inflammation associated with SSc.     

Altered B lymphocyte homeostasis and functions in systemic sclerosis

Beyond the production of autoantibodies, B-cells are thought to play a role in systemic sclerosis (SSc) by secreting proinflammatory/profibrotic cytokines. B-cells are a heterogeneous population with different subsets distinguished by their phenotypes and cytokine production. Data about B-cell subsets, cytokine production and intracellular pathways leading to this production are scarce in SSc. The aim of our study was to describe B-cell homeostasis, activation, proliferation, cytokine production in B-cells and serum and B-cell intracellular signaling pathways in SSc. We hypothezided that B-cell homeostasis and cytokine production were altered in SSc and could be explained by serum cytokine as well as by intracellular signaling pathway abnormalities.Forty SSc patients and 20 healthy controls (HC) were prospectively included. B-cell subsets were determined by flow cytometry using CD19, CD21, CD24, CD38, CD27, IgM and IgD. CD25, CD80, CD95, HLA-DR were used to assess B-cell activation. Intracellular production of IL-10 and IL-6 were assessed by flow cytometry after TLR9 and CD40 stimulation. IL-6, IL-10, Ki67, Bcl2 mRNA were quantified in B-cells. Cytokine production was also assessed in sera and supernatants of B-cell culture, using a multiplex approach. Signaling pathways were studied through phosphorylation of mTOR, ERK, STAT3, STAT5 using a flow cytometry approach.We found that SSc patients exhibited an altered peripheral blood B-cell subset distribution, with decreased memory B-cells but increased proportion of naive and CD21^LoCD38^Lo B-cell subsets. We observed an increased expression of activation markers (CD80, CD95, HLA-DR) on some B-cell subsets, mainly the memory B-cells. Secretion of IL-6, BAFF and CXCL13 were increased in SSc sera. There was no correlation between the peripheral blood B-cell subsets and the serum concentrations of these cytokines. After stimulation, we observed a lower proportion of IL-10 and IL-6 producing B–cells in SSc. Finally, we observed a significant decrease of mTOR phosphorylation in SSc patient B-cells.In conclusion, we observed an altered B-cell homeostasis in SSc patients compared to HC. Memory B-cells were both decreased and activated in patients. IL-10 producing B-cells were decreased in SSc. This decrease was associated with an alteration of mTOR phosphorylation in B-cells. Conversely, there was no correlation between serum cytokine profile and B-cell homeostasis alterations.     

Clinical and serological associations with anti-RNA polymerase antibodies in systemic sclerosis.

There are three classes of RNA polymerase enzyme (RNAPs I, II and III). In systemic sclerosis (SSc), three main groups of anti-RNAP sera have been characterized by radioimmunoprecipitation techniques: anti-RNAP I/III sera, anti-RNAP I/II/III sera, and a group precipitating both RNAP II and topoisomerase I (topo I). Some sera in this third group precipitate the phosphorylated (IIO) form of RNAP II in the absence of the unphosphorylated (IIA) form. Certain other antinuclear antibodies (ANA) have also been detected in anti-RNAP IIO/IIA/topo I and anti-RNAP IIO/topo I sera. In the present study of 155 SSc patients, clinical features of individuals from each of these antibody groups were assessed and compared with those of patients from other autoantibody-defined groups. The anti-RNAP I/II/III antibody specificity was closely associated with the presence of diffuse cutaneous SSc (dc-SSc) (77.8%; cf. remaining group, 12.4%; P < 0.001; relative risk (RR) 6.3). Patients with anti-RNAP I/III antibodies also had an increased incidence of dc-SSc, but this was not significant (42.9%; cf. remainder, 15.7%). Anti-RNAP+ patients had a significantly increased incidence of renal involvement (29.0%, cf. remainder, 11.3%; P < 0.05; RR 2.6), with 40% of anti-RNAP I/II/III patients having renal disease. Meanwhile, the presence of anti-centromere antibodies (ACA) was associated with limited cutaneous SSc (lc-SSc) (100.0%; cf. remainder, 75.3%; P < 0. 005), together with reduced incidences of both renal disease (2.4%, cf. remainder, 22.1%: P < 0.01) and pulmonary fibrosis (21.4%, cf. remainder, 52.3%; P < 0.005; RR 1.9). Anti-topo I antibodies were associated with the presence of pulmonary fibrosis (69.7%; cf. remainder, 32.6%; P < 0.001; RR 2.1). A majority of anti-topo I sera were from lc-SSc patients, regardless of whether anti-topo I antibodies occurred alone (75.0%) or together with anti-RNAP IIO + IIA antibodies (75.0%), and this was similar to the remainder (86. 5%; NS). However, when anti-topo I+ patients were compared with the ACA group, and then with all anti-RNAP I+ patients (37.5% lc-SSc), significant differences were found in the occurrence of dc- versus lc-SSc (P < 0.005 and P < 0.05, respectively). In conclusion, these results confirm that there are three main groups of SSc sera, each characterized by the presence of a mutually exclusive SSc-specific autoantibody (ACA, anti-topo I or anti-RNAP I), and distinguished by patterns of cutaneous involvement and specific clinical features. It appears that, in each of the three groups of SSc patients, distinct pathological processes are occurring, which are responsible for the characteristic symptoms, for the modification of particular autoantigens and, consequently, for the production of particular autoantibodies. Based on these data, together with our previous results, it is further hypothesized that anti-RNAP II antibodies may be produced in the context of two different immune response pathways.     

Expression of cytokine and chemokine genes in Epstein-Barr virus-associated nasopharyngeal carcinoma: comparison with Hodgkin's disease

Nasopharyngeal carcinoma (NPC) and Hodgkin's disease (HD) are characterized by their association with Epstein-Barr virus (EBV) and the presence of an intense lymphoid stroma, consisting of T lymphocytes and other reactive cells. In both entities, the tumour cells express viral proteins known to provide target epitopes for cytotoxic T-cells (CTLs), yet in vivo, the tumour cells appear to escape CTL recognition. A comparative in situ hybridization study of cytokine and chemokine gene expression in NPC and HD has been undertaken, focusing on cytokines which are known to be inducible by EBV in vitro. Hodgkin and Reed-Sternberg (HRS) cells expressed interleukin (IL)-6, IL-8, and IL-10, and the thymus and activation regulated chemokine (TARC) in 15/22, 0/22, 5/22, and 16/21 cases, respectively. In NPC, the epithelial tumour cells showed expression of IL-6 in 3/43 cases and of IL-8 in 2/40 cases. There was no detectable expression of IL-10 and TARC in these cases. These data confirm that HRS cells frequently express cytokine and chemokine genes and suggest that this may enable HRS cells to modulate the immune response in their microenvironment and to escape CTL detection. In contrast, NPC tumour cells show only rare expression of IL-6 and IL-8 and no detectable expression of IL-10 and TARC. Thus, the results suggest that the mechanisms employed by the EBV-positive tumour cells to escape immune recognition and destruction differ between HD and NPC.     

Measuring and managing appearance anxiety in patients with systemic sclerosis

Introduction: Systemic sclerosis (SSc, scleroderma) is a progressive, autoimmune, connective tissue disease of unknown etiology that can cause changes in appearance in socially important areas of the body (e.g. face and hands). Social concerns related to changes in appearance can contribute to anxiety specific to situations where one’s appearance will be evaluated, or appearance anxiety. Appearance anxiety is a relevant but underexplored construct in SSc.

Areas covered: We review the current knowledge on appearance anxiety in SSc, including assessment of the construct and interventions. Relevant references in the field were obtained through a literature search in MEDLINE/PubMed and PsycINFO for articles published through September 2018.

Expert commentary: There is a dearth of research in the SSc literature examining the construct of appearance anxiety. A growing interest in appearance anxiety in SSc has led to several relevant measures being validated in this population, including the Social Appearance Anxiety Scale. Important areas for future research are the development of interventions to address appearance anxiety and the use of randomized controlled trials to evaluate these interventions.     

Ocular findings in patients with systemic sclerosis

OBJECTIVE:

To evaluate the frequency and characteristics of ocular manifestations in outpatients with systemic sclerosis.

METHODS:

In this cross-sectional study, 45 patients with systemic sclerosis were enrolled. Data regarding demographics, disease duration and subtype, age at diagnosis, nailfold capillaroscopic pattern and autoantibody profile were collected, and a full ophthalmic examination was conducted. Parametric (Student''s t-test) and nonparametric (Mann-Whitney U test) tests were used to compare continuous variables. Fisher''s exact test was used to compare categorical data. P values < 0.05 were considered significant.

RESULTS:

Twenty-three subjects (51.1%) had eyelid skin changes; 22 (48.9%) had keratoconjunctivitis sicca, 19 (42.2%) had cataracts, 13 (28.9%) had retinal microvascular abnormalities and 6 (13.3%) had glaucoma. Eyelid skin changes were more frequent in patients with the diffuse subtype of systemic sclerosis and were associated with a younger age and an earlier age at diagnosis. Cataracts were presumed to be age-related and secondary to corticosteroid treatment. There was no association between demographic, clinical or serological data and keratoconjunctivitis sicca. The retinal microvascular abnormalities were indistinguishable from those related to systemic hypertension and were associated with an older age and a severe capillaroscopic pattern.

CONCLUSIONS:

Eyelid skin abnormalities and keratoconjunctivitis sicca were the most common ocular findings related to systemic sclerosis. Some demographic and clinical data were associated with some ophthalmic features and not with others, showing that the ocular manifestations of systemic sclerosis are characterized by heterogeneity and reflect the differences in the implicated pathophysiological mechanisms.     

Monocyte-derived RANTES is intrinsically elevated in periodontal disease while MCP-1 levels are related to inflammation and are inversely correlated with IL-12 levels

Bacteria colonizing tooth surfaces are essential in the induction of an inflammatory response in the periodontal tissues, but do not cause periodontitis in everyone, implicating differences in the host immune response. These possible differences were studied using lipopolysaccharide (LPS)-stimulated whole blood cell cultures (WBCC), which revealed a down regulation of monocyte derived interleukin-12 (IL-12p70) in untreated periodontitis patients and an up regulation after therapy. IL-12p70 is a crucial factor in the differentiation of Th1 cell responses. Since CC chemokines are able to influence the T cell differentiation via cytokine secretion in antigen-presenting cells, the production of CC chemokines in periodontitis was evaluated. Therefore WBCC were stimulated with LPS from Escherichia coli for 18 h and the levels of IL-12p70 and CC chemokines were measured in the supernatants by ELISA. Untreated periodontitis patients released 2 fold more RANTES (regulated on activation normal T cell expressed and secreted) (P = 0.01) and lower levels of IL-12p70 in comparison to controls (P < 0.05). A trend towards higher levels of macrophage chemoattractant protein-1 (MCP-1) (P = 0.07) was also seen in untreated periodontitis patients; while similar levels of monocyte derived chemokine (MDC) and macrophage inflammatory proteins-1 alpha and -1 beta (MIP-1 alpha and -1 beta) were found. After periodontal therapy no changes were seen with regard to MDC, MIP-1 alpha, MIP-1 beta and RANTES, whereas the MCP-1 levels decreased (P < 0.05) and the IL-12p70 levels strongly increased (P < 0.01). The data showed a consistent inverse correlation between the levels of MCP-1 and IL-12p70, and their proportional changes after therapy correlated with the clinical inflammatory response after therapy. This indicates that the disease state regulates the release of IL-12p70 and MCP-1 in E. coli LPS-stimulated WBCC. In contrast, the persistent augmented levels of RANTES after therapy are suggestive for an intrinsic behaviour.     

Circulating levels of soluble CD30 are increased in patients with systemic sclerosis (SSc) and correlate with serological and clinical features of the disease

Activated Th2 lymphocytes express the surface molecule CD30 and release a soluble form of the same molecule which can be detected both in vivo and in vitro. In the present study, high levels of soluble CD30 were found in the peripheral blood of patients with SSc, and a significant correlation with skin score and erythrocyte sedimentation rate (ESR) was detected. Furthermore, we observed a higher spontaneous release of soluble CD30 in the supernatants of unstimulated cultures of peripheral blood mononuclear cells from our patients compared with healthy controls. Taken together, these data suggest a possible involvement of Th2 cells in the immunopathogenesis of SSc, and the dosage of CD30 soluble in the peripheral blood may be helpful in following the outcome of the disease.     

Antiviral effect of nicotinamide on enterovirus‐infected human islets in vitro: Effect on virus replication and chemokine secretion

Type 1 diabetes is a chronic disease characterized by the selective destruction of insulin‐producing cells in the pancreas. Enterovirus (EV) is the prime candidate to initiate this destruction and several inflammatory chemokines are induced by EV infection. Nicotinamide has been shown to protect isolated human islets, and to modulate chemokine expression. The aim of this study was to evaluate the effect of nicotinamide on EV replication and EV‐induced chemokine secretion and cytolysis of human islets. Two EV strains were used to infect human islets in vitro, one lytic (Adrian) isolated from a child at onset of type 1 diabetes, and one non‐lytic (VD2921). Secretion of the chemokines IP‐10 and MCP‐1, viral replication, and virus‐induced cytopathic effect (CPE), were measured at different time points post‐infection. Addition of nicotinamide to the culture medium reduced viral replication and virus‐induced islet destruction/CPE, significantly. Both EV strains increased secretion of IP‐10 and MCP‐1, when measured days 2–3, and days 5–7 post infection, compared to mock‐infected control islets. IP‐10 was not produced by uninfected isolated islets, whereas a basal secretion of MCP‐1 was detected. Interestingly, addition of nicotinamide blocked completely (Adrian), or reduced significantly (VD2921), the virus‐induced secretion of IP‐10. Secretion of MCP‐1 was also reduced in the presence of nicotinamide, from infected and uninfected islets. The reported antiviral effects of nicotinamide could have implications for the treatment/prevention of virus‐ and immune‐mediated disease. Also, this study highlights a possible mechanism of virus‐induced type 1 diabetes through the induction of MCP‐1 and IP‐10 in pancreatic islets. J. Med. Virol. 81:1082–1087, 2009. © 2009 Wiley‐Liss, Inc.     

Histopathological changes of cervical tissue in women with systemic sclerosis

Systemic sclerosis is a connective tissue disease that can affect almost any organ of the body. The clinical aspects of systemic sclerosis on the reproductive system have been studied in large series, and an increased rate of cesarean section has been reported. For this reason, in the present study the histopathological features of cervical specimens of hysterectomyzed women with systemic sclerosis were evaluated. An increased frequency of vascular and stromal abnormalities in cervical specimens of women with systemic sclerosis were observed. Vascular medial hypertrophy, intimal thickening, and fibrosis were more often encountered in the cervical specimens of the patients with systemic sclerosis. Some of the histopathological features also showed correlation with the clinical profile of the disease. The patients with vascular medial hypertrophy in their cervical specimens were older, had a higher Rodnan score, and had longer duration of the disease. In contrast to vascular medial hypertrophy, periadventitial edema was found in the cervical specimens of the patients who were younger, had a lower Rodnan score, and had shorter duration of the disease. It was concluded that the problems that are seen in common obstetric and gynecological practices in patients with systemic sclerosis may be explained by these tissue abnormalities.