Potential role of tumor-associated macrophages and CD163/CD68 ratio in mycosis fungoides and Sézary syndrome in correlation with serum sCD163 and CCL22.

Currently, there are no curative treatment options for mycosis fungoides (MF) and Sézary syndrome (SS) other than stem cell transplant. Understanding the interplay between tumor cells and tumor microenvironment could aid in the development of new therapies. Tumor-associated macrophages (TAMs) mostly have M2 phenotype that promotes tumor progression. This study investigated CD68+ and CD163+ TAMs as well as CD163/CD68 ratio in skin lesions from different stages of MF, large-plaque parapsoriasis, and SS. Moreover, we analyzed serum levels of sCD163 and CCL22 in correlation with TAMs count and CD163/CD68 ratio. CD68+ and CD163+ TAMs count significantly increased as the disease progressed. CD163/CD68 ratio was highest at MF tumor stage and SS indicating M2 polarization with disease progression. Significant positive correlations were detected between serum levels of sCD163 and CCL22 and CD68+ and CD163+ TAMs count and CD163/CD68 ratio. We concluded that TAMs play an important role in MF progression. High CD163/CD68 ratio in tumor stage MF and SS indicates M2 polarization of TAMs with tumor progression. CD163/CD68 ratio should be considered in assessing TAMs rather than total TAMs count. Also, sCD163 and CCL22 serum levels reflect M2 load and thus could be used as markers to assess disease progression.

Can moderate-intensity aerobic exercise ameliorate atopic dermatitis?

It has been shown that aerobic exercise improves atopic dermatitis (AD), although the mechanism is not clear. Here, we propose a hypothesis that moderate-intensity aerobic exercise improves AD in a mouse model through modulating allergic inflammation. The DNCB-treated mouse model for eczema was divided into 3 groups: (a) not subjected to aerobic exercise, (b) subjected to continuous aerobic exercise and (c) subjected to accumulated aerobic exercise. After given exercise using a treadmill device either 30 min/d or 10 min × 3/day at a speed of 16 m/min, for 9 days, respectively, dermatitis symptom score, thickness of epidermis/dermis and eosinophil infiltration were decreased in the 2 exercise groups compared to the sedentary living group. The serum levels of IgE, MCP-1 and MDC showed a significant decrease both in the continuous or accumulated exercise groups. Moderate-intensity aerobic exercise ameliorates dermatitis symptoms through immune modulation in the DNCB-treated mouse model for eczema.

Teneligliptin, a DPP-4 Inhibitor, Decreases Plasma Levels of Inflammatory Chemokines During a Standard Meal Test in Patients With Type 2 Diabetes.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) rapidly inactivates incretin hormones and several chemokines, thus influencing chemokine function. There have recently been several reports that DPP-4 inhibitor therapy is associated with an increased risk of bullous pemphigoid (BP), an autoimmune skin disease. Previous studies have demonstrated an increase of CCL11/Eotaxin, a DPP-4 substrate, in serum and blister fluid from patients with BP. Serum levels of CCL22/macrophage-derived chemokine (MDC) and CXCL10/IP-10, other DPP-4 substrates, are also elevated in BP patients. MATERIALS AND METHODS: In patients with type 2 diabetes, we investigated the effect of treatment with teneligliptin (a DPP-4 inhibitor) for 24 weeks on plasma levels of CCL11/Eotaxin, CCL22/MDC and CXCL10/IP-10 during a meal test. Ten consecutive patients with type 2 diabetes who showed inadequate glycemic control by metformin and/or sulfonylureas were recruited. A standard meal test was performed at baseline and after 24 weeks of treatment with teneligliptin at 20 mg/day. Blood samples were collected at 0, 30, 60 and 120 minutes after ingestion of the meal. In addition to plasma levels of the 3 chemokine, plasma DPP-4 enzyme activity and soluble DPP-4 antigen were measured. RESULTS: Treatment with teneligliptin decreased hemoglobin A1c and reduced fasting plasma DPP-4 activity by 90.1% compared with baseline. Unexpectedly, plasma levels of all 3 chemokines (including CCL11/Eotaxin) were not increased after teneligliptin treatment, and instead were significantly lower at every point during the meal test. CONCLUSIONS: Teneligliptin reduced the plasma concentrations of 3 chemokines (DPP-4 substrates) that may be related to the occurrence of DPP4 inhibitor-associated BP (UMIN000012508).

In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.

Serum and plasma contain abundant biological information that reflect the body's physiological and pathological conditions and are therefore a valuable sample type for disease biomarkers. However, comprehensive profiling of the serological proteome is challenging due to the wide range of protein concentrations in serum. Methods: To address this challenge, we developed a novel in-depth serum proteomics platform capable of analyzing the serum proteome across ~10 orders or magnitude by combining data obtained from Data Independent Acquisition Mass Spectrometry (DIA-MS) and customizable antibody microarrays. Results: Using psoriasis as a proof-of-concept disease model, we screened 50 serum proteomes from healthy controls and psoriasis patients before and after treatment with traditional Chinese medicine (YinXieLing) on our in-depth serum proteomics platform. We identified 106 differentially-expressed proteins in psoriasis patients involved in psoriasis-relevant biological processes, such as blood coagulation, inflammation, apoptosis and angiogenesis signaling pathways. In addition, unbiased clustering and principle component analysis revealed 58 proteins discriminating healthy volunteers from psoriasis patients and 12 proteins distinguishing responders from non-responders to YinXieLing. To further demonstrate the clinical utility of our platform, we performed correlation analyses between serum proteomes and psoriasis activity and found a positive association between the psoriasis area and severity index (PASI) score with three serum proteins (PI3, CCL22, IL-12B). Conclusion: Taken together, these results demonstrate the clinical utility of our in-depth serum proteomics platform to identify specific diagnostic and predictive biomarkers of psoriasis and other immune-mediated diseases.

Increased Plasma Levels of the TH2 chemokine CCL18 associated with low CD4+ T cell counts in HIV-1-infected Patients with a Suppressed Viral Load.

The chemokine (C-C motif) chemokine ligand 18 (CCL18) is a structural homolog of CCL3 primarily produced by monocyte-derived cells with an M2 phenotype. Elevated levels of CCL18 have been observed in several diseases associated with malignancies and chronic inflammation. The role of CCL18 in Human Immunodeficiency Virus (HIV-1) infection remains unknown. We analyzed expression levels of T helper cell-mediated (TH2) chemokines CCL18, CCL17, and CCL22 by ELISA in plasma collected from HIV-1-infected and healthy donors. In HIV-1-infected individuals, plasma viral loads were monitored by NucliSense HIV-1 QT assay and T cell counts and expression of the activation marker CD38 were determined by flow cytometry. Our data showed a significant increase in plasma levels of CCL18 in HIV-1-infected individuals compared to uninfected controls (p < 0.001) and a significant correlation between CCL18 levels and viral load in untreated patients. No significant difference of CCL18 levels was detected among the HIV-1-infected patients treated with combined antiretroviral therapy (cART) and HIV-1-untreated patients.CCL18 values are negatively correlated with CD4+CD38+ cell numbers and total CD4+ T cell counts in patients with a suppressed viral load. Notably, plasma levels of the TH2 chemokines CCL17 and CCL22 are also elevated during HIV-1 infection. However, no correlation of CCL17 and CCL22 production with CD4+ T cell counts was detected. Presented data shows that the chemokines, CCL17, CCL18, and CCL22 are increased during HIV-1 infection. However, only increased levels of CCL18, a marker of M2 macrophages, correlate with low CD4+ T cell counts in patients with suppressed viral load, raising the possibility that CCL18 and/or CCL18-producing cells may interfere with their reconstitution in HIV-1-infected patients on cART.

Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study.

Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)-positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Increased peripheral levels of TARC/CCL17 in first episode psychosis patients.

BACKGROUND: Evidence for a link between the pathophysiology of schizophrenia and the immune system is mounting. Altered levels of chemokines in plasma have previously been reported in patients with schizophrenia under antipsychotic medication. Here we aimed to study both peripheral and central chemokine levels in drug-naïve or short-time medicated first episode psychosis (FEP) patients. METHOD: We analyzed nine chemokines in plasma and CSF from 41 FEP patients and 22 healthy controls using electrochemiluminescence assay. RESULTS: In plasma four chemokines; TARC/CCL17, eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 and in CSF one chemokine; IP-10/CXCL10 showed reliable detection in >50% of the cases. FEP patients displayed increased levels of TARC/CCL17 in plasma compared to healthy controls, 89.6 (IQR 66.2-125.8) pg/mL compared to 48.6 (IQR 28.0-71.7) pg/mL (p = 0.001). The difference was not attributed to confounding factors. Plasma TARC/CCL17 was not associated with PANSS, CGI or GAF scores, neither with cognitive functions. The chemokines eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 in plasma and IP-10/CXCL10 in CSF did not differ between FEP patients and controls. CONCLUSION: In line with a previous study showing that chronic patients with schizophrenia display increased plasma TARC/CCL17 levels, we here found an elevation in FEP patients suggesting a role of TARC/CCL17 in early stages of schizophrenia. The exact mechanism of this involvement is still unknown and future longitudinal studies as well as studies of central and peripheral chemokine levels would be of great interest.

Low Mother-to-Child CCL22 Chemokine Levels Are Inversely Related to Mite Sensitization and Asthma in Early Childhood.

Few studies have addressed the mother-to-child transmission of Th2 immunity and the impact on the development of atopic diseases in early childhood. We investigated 186 children who were followed-up regularly for 4 years in a birth cohort study. The levels of Th2 related chemokine (C-C motif) ligand 17 (CCL17) and CCL22 were quantified in cord blood and at 1.5 years-of-age using multiplex Luminex kits. The levels of 125 pairs of CCL17 and CCL22 chemokines from birth to 1.5 years were recorded in this study. Using K-means clustering, only the declining trend of CCL22 levels was separately clustered (cluster A, n = 51; cluster B, n = 46; cluster C, n = 28). Mothers of children with higher CCL22 chemokine levels at birth were significantly more likely to display Dermatophagoides pteronyssinus sensitization. A lower CCL22 level at birth with a slight rise during infancy was associated with higher prevalence of mite sensitization and a higher risk of asthma at 3 years-of-age (P = 0.014). In conclusion, low mother-to-child Th2-associated chemokine CCL22 levels appear to be inversely related to mite sensitization and the risk of asthma development in early childhood.

Industrial hog farming is associated with altered circulating immunological markers.

OBJECTIVES: The previously observed inverse association between hog farming and risk of lung cancer in the Agricultural Health Study (AHS) has been attributed to endotoxin exposure, the levels of which are particularly high in industrial hog confinement facilities. We conducted an investigation to explore the potential biological mechanisms underlying this association, as well as other immunological changes associated with hog farming. METHODS: Serum immune marker levels were measured using a multiplexed bead-based assay in 61 active hog farmers and 61 controls matched on age, phlebotomy date and raising cattle. Both groups comprised non-smoking male AHS participants from Iowa. We compared natural log-transformed marker levels between hog farmers and controls using multivariate linear regression models. RESULTS: Circulating levels of macrophage-derived chemokine (CCL22), a chemokine previously implicated in lung carcinogenesis, were reduced among hog farmers (17% decrease; 95% CI -28% to -4%), in particular for those with the largest operations (>6000 hogs: 26% decrease; 95% CI -39% to -10%; ptrend=0.002). We also found that hog farmers had elevated levels of other immune markers, including macrophage inflammatory protein-3 alpha (MIP-3A/CCL20; 111% increase, 95% CI 19% to 273%), basic fibroblast growth factor (FGF-2; 93% increase, 95% CI 10% to 240%) and soluble interleukin-4 receptor (12% increase, 95% CI 1% to 25%), with particularly strong associations for MIP-3A/CCL20 and FGF-2 in winter. CONCLUSIONS: These results provide insights into potential immunomodulatory mechanisms through which endotoxin or other exposures associated with hog farming may influence lung cancer risk, and warrant further investigation with more detailed bioaerosol exposure assessment.

Macrophage-Derived Chemokine: A Putative Marker of Pharmacological Therapy Response in Major Depression?

INTRODUCTION: Inflammatory processes play an important and complex role in the pathophysiology of major depressive disorder (MDD), but, so far, no specific investigation of chemokines exists. METHODS: In this study, we investigated the changes of plasma chemokine levels (eotaxin-1, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1ß, and TARC) in 47 MDD patients before (PRE) and after 1 and 6 weeks of pharmacological treatment (POST1 and POST6) in relation to the response to antidepressive therapy. We hypothesized that the direction of alterations in levels of chemokines would significantly differ between the 2 groups, responders and nonresponders. RESULTS: Among the investigated chemokines, only the level of macrophage-derived chemokine (MDC) changed significantly in relation to therapy response. MDC levels were significantly elevated in the responder group at POST6. DISCUSSION: MDC is a constitutively expressed chemokine involved in the pathophysiology of infectious and neoplastic diseases. This is the first study providing valuable hints that MDC might serve as a marker of pharmacological therapy response in MDD.

C-C motif chemokine 22 ligand (CCL22) concentrations in sera of gastric cancer patients are related to peritoneal metastasis and predict recurrence within one year after radical gastrectomy.

BACKGROUND: Gastric cancer is a common cancer with a poor prognosis. Chemokines play important roles in the tumor microenvironments to support tumor growth and metastasis. The effects of C-C motif chemokine ligand 22 (CCL22) in gastric cancer remain unclear. MATERIALS AND METHODS: Between January 1, 2014 and April 31, 2014, a total of 298 gastric cancer patients were recruited to this study. Circulating concentrations of CCL22 were measured in gastric cancer patients before surgery, at discharged and during follow-up visits. The expression of CCL22 in gastric cancer tumor beds was measured by immunohistochemistry. The proportion of CD3+CD4+CD25+Foxp3+ regulatory T cells in tumor sites was assessed by flow cytometry. RESULTS: Gastric cancer patients had higher serum CCL22 levels compared to healthy controls (P < 0.001). Immunohistochemistry indicated that the gastric cancer tumor beds were the source of serum CCL22, as gastric cancer patients had an increased proportion of strong expression of CCL22 (P < 0.01), and immunohistochemistry scores were positively correlated with levels of circulating CCL22 (P < 0.001). Gastric cancer tissue harbored a higher percentage of regulatory T cells compared to normal tumor-free stomach margins (P < 0.001), and this abundance of regulatory T cells was positively correlated with circulating levels of CCL22 (P < 0.001). Gastric cancer patients with peritoneal metastasis showed increased levels of circulating CCL22 before surgery compared to metastasis-free patients (P < 0.001). Gastric cancer patients with the recurrence within the first year after surgery had elevated serum CCL22 concentrations at different time points compared to those of recurrence-free patients (P < 0.001). Logistic regression analysis indicated that high CCL22 circulating levels before surgery is a risk factor for peritoneal metastasis and an independent risk factor for an early recurrence after surgery. CONCLUSIONS: CCL22 plays an important role in supporting gastric cancer development presumably by increasing the percentage of regulatory T cells in the tumor microenvironments. CCL22 levels in sera have a predictive value for gastric cancer peritoneal metastasis and the early recurrence. Therefore, CCL22 may be a therapeutic target for gastric cancer.

Immune markers of social cognitive bias in schizophrenia.

Social cognition is impaired in schizophrenia, is relatively independent of purely neurocognitive domains such as attention and executive functioning, and may be the strongest predictor of functional outcome in this disease. Within a motivated reasoning framework, we tested the hypothesis that the anti-inflammatory Th2-associated cytokines, IL-10 and MDC, would be correlated with behavioral measures of social cognitive threat-detection bias (self-referential gaze detection bias and theory of mind (ToM) bias) in delusional versus non-delusional patients. We administered to schizophrenia patients with delusions (n=21), non-delusional patients (n=39) and controls (n=20) a social cognitive task designed to be sensitive to psychosocial stress response (the Waiting Room Task) and collected plasma levels of inflammatory markers using a bead-based flow immunoassay. Results partially supported our hypothesis. The anti-inflammatory cytokine IL-10 was associated with self-referential ToM bias in the delusional cohort as predicted, and not with non-delusional patients or healthy controls. This bias reflects a documented tendency of schizophrenia patients with delusions to excessively attribute hostile intentions to people in their environment. Since this cytokine correlated only with ToM bias and only in delusional patients, elevated levels of this cytokine in the blood may eventually serve as a useful biomarker distinguishing delusional patients from both non-delusional patients and healthy controls.

Urinary Microbiome and Cytokine Levels in Women With Interstitial Cystitis.

OBJECTIVE: To investigate differences in the urinary microbiome and cytokine levels between women with and without interstitial cystitis and to correlate differences with scores on standardized symptom severity scales and depression and anxiety screening tools. METHODS: Our cross-sectional study compared women presenting to a pelvic floor clinic and diagnosed with interstitial cystitis over a 6-month period with age-matched women in a control group from the same institution. Participants provided a catheterized urine sample and completed symptom severity, quality-of-life, depression, and anxiety screening questionnaires. Urinary microbiomes generated through bacterial ribosomal RNA sequencing and cytokine levels were analyzed using a standard immunoassay. Nonparametric analyses were used for all comparisons. RESULTS: Participants with interstitial cystitis reported more disability, bothersome urinary symptoms, genitourinary pain, and sexual dysfunction and scored higher on depression and anxiety screens compared with women in the control group. The urine of participants with interstitial cystitis contained fewer distinct operational taxonomic units (2 [median range 2-7, interquartile range 1] compared with 3.5 [median, range 2-22, interquartile range 5.25], P=.015) and was less likely to contain Lactobacillus acidophilus (1/14 [7%] compared with 7/18 [39%], P=.05) compared with women in the control group. L acidophilus was associated with less severe scores on the Interstitial Cystitis Symptoms Index (1 [median, range 0-17, interquartile range 5] compared with 10 [median, range 0-14, interquartile range 11], P=.005) and the Genitourinary Pain Index (0 [median, range 0-42, interquartile range 22] compared with 22.5 [median, range 0-40, interquartile range 28], P=.03). Participants with interstitial cystitis demonstrated higher levels of macrophage-derived chemokine (13.32 [median, range 8.93-17.05, interquartile range 15.86] compared with 0 [median, range 8.93-22.67, interquartile range 10.35], P=.037) and interleukin-4 (1.95 [median, range 1.31-997, interquartile range 11.84] compared with 1.17 [median, range 0.44-3.26, interquartile range 1.51], P=.029). There was a positive correlation between interleukin-4 and more severe scores on the Interstitial Cystitis Symptoms Index (r=0.406, P=.013). No associations between the presence of lactobacillus species and cytokine levels were observed. CONCLUSION: The urinary microbiome of participants with interstitial cystitis was less diverse, less likely to contain Lactobacillus species, and associated with higher levels of proinflammatory cytokines. It is unknown whether this represents causality and whether the effect of alterations to the urinary microbiome is mediated through an inflammatory response.

High cord blood CCL22/CXCL10 chemokine ratios precede allergic sensitization in early childhood.

Atopic diseases are known to be characterized by a T helper (Th) 2-skewed immunity; however, there are few studies addressing the Th1/Th2 immunity at birth related to the development of atopic diseases in early childhood. We investigated 186 children followed up regularly at the clinic for 4 years in a birth cohort study. The Th1-associated CXC chemokine ligand (CXCL)-10, CXCL11, and the Th2-associated CC chemokine ligand (CCL)-17 and CCL22 were quantified in cord blood by multiplex Luminex kits. Specific immunoglobulin E antibodies against food and inhalant allergens were measured at 6 months as well as 1, 1.5, 2, 3, and 4 years of age. Cord blood CCL22 levels were positively associated with IgE sensitization at age 2, whereas cord blood CXCL10 levels were negatively associated with mite sensitization at age 3. Furthermore, a high cord blood CCL22/CXCL10 chemokine ratio was significantly associated with a higher risk of allergic sensitization at age 3 (OR, 1.02; 95% confidence interval [CI], 1.005-1.039; P = 0.012). However, cord blood Th1- and Th2-associated chemokines and their ratios were not associated with atopic diseases at different age. Our study indicates that a Th2-skewed immunity at birth may increase risk of allergic sensitization but not of allergic outcomes later in life.

MDC and BLC are independently associated with the significant risk of early stage lung adenocarcinoma.

BACKGROUND: This prospective study was designed to investigate the association between ten circulating inflammatory biomarkers and the risk for early stage lung adenocarcinoma. METHODS: All inflammatory biomarkers were measured in 228 patients with early stage (IA to IIB) lung adenocarcinoma and 228 age-, sex- and smoking-matched healthy controls by using the Luminex bead-based assay. RESULTS: Only two biomarkers were significantly associated with the risk of early stage lung adenocarcinoma after the Bonferroni correction: the multivariate odd ratio (OR) (95% confidence interval or CI) was 0.29 (0.16-0.53) for MDC and 4.17 (2.23-7.79) for BLC for the comparison of patients in the 4th quartile with the 1st quartile (both P<0.0001). When analysis was restricted to never smokers (196 patients/196 controls), MDC and BLC were still significantly associated with the risk of early stage lung adenocarcinoma (OR, 95% CI, P: 0.37, 0.21-0.66, P<0.0001 for MDC and 2.78, 1.48-5.22, P =0.001 for BLC). Furthermore, elevated BLC was associated with a 2.90-fold (95% CI: 1.03-8.17, P=0.037) increased risk of subcentimeter lung adenocarcinoma, and there was an increasing trend for BLC with the progression of subcentimeter lung adenocarcinoma. CONCLUSION: Our findings demonstrated that MDC and BLC were independently associated with the significant risk of early stage lung adenocarcinoma, even in non-smokers and in stage IA patients. BLC was further identified to play a carcinogenic role in the progression of lung adenocarcinoma.

Higher circulating levels of chemokines CXCL10, CCL20 and CCL22 in patients with ischemic heart disease.

Recruitment of leukocytes is one of the earliest events in the pathogenesis of ischemic heart disease (IHD) and chemokines play an important role in the migration of these cells into the inflammation sites. The aim of this study was to evaluate the CXCL10, CCL20 and CCL22 levels and the single nucleotide polymorphisms (SNPs) rs4508917, rs6749704 and rs4359426 in chemokine genes in patients with IHD to clarify any association. A total of 300 patients with IHD as having acute myocardial infarction (AMI; n=100), stable angina (SA; n=100) or unstable angina (UA; n=100) and 100 healthy subjects as a control group were enrolled to study. Serum samples from all participants were tested for the CXCL10, CCL20 and CCL22 levels by using ELISA. The SNPs were determined by polymerase chain reaction-restriction length polymorphism (PCR-RFLP) method. The mean serum concentrations of CXCL10, CCL20 and CCL22 in AMI patients (395.97±21.20Pg/mL, 108.38±10.31Pg/mL and 1852.58±205.77Pg/mL), SA patients (405.48±27.36Pg/mL, 90.20±7.69Pg/mL and 2322.04±231.23Pg/mL) and UA patients (396.69±22.79Pg/mL, 141.87±18.10Pg/mL and 2754.89±211.70Pg/mL) were significantly higher than in the healthy group (179.38±8.85Pg/mL, 51.92±4.62Pg/mL and 451.82±23.76Pg/mL, respectively; P<0.001). Similarly, the serum levels of CXCL10, CCL20 and CCL22 in total IHD patients (399.38±13.77Pg/mL, 113.49±7.48Pg/mL and 2309.84±126.39Pg/mL, respectively) were also significantly higher as compared with healthy subjects (P<0.001). The serum levels of CCL20 and CCL22 in UA patients were significantly higher than those in SA and AMI patients, respectively (P<0.01 and P<0.003, respectively). The serum levels of CXCL10 and CCL20 in diabetic patients were significantly higher in comparison to non-diabetic patients (P<0.05 and P<0.02, respectively). The serum levels of CCL22 in dyslipidemic- and obese patients were also significantly higher in comparison with non-dyslipidemic- and non-obese patients, correspondingly (P<0.05 and P<0.01, respectively). There were no significant differences between men and women or between patients who treated with statin, aspirin, ß-blockers or angiotensin converting enzyme (ACE) inhibitors and patients without mentioned treatment regarding the levels of chemokines. The frequency of the GG genotype at SNP rs4508917 in CXCL10 gene was higher, whereas the frequency of the AA genotype at SNP rs4359426 in CCL22 gene was lower in total patients with IHD as compared with healthy subjects (P<0.04 and P<0.002, respectively). These results showed that the higher levels of CXCL10, CCL20 and CCL22 were associated with IHD. The serum levels of chemokines may influence by the certain traditional risk factors of IHD and some studied SNPs, but did not influence by treatment and gender of patients.

Aberrant Expression of Bacterial Pattern Recognition Receptor NOD2 of Basophils and Microbicidal Peptides in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease, associated with basophil infiltration into skin lesions and Staphylococcus aureus (S. aureus)-induced inflammation. Pattern recognition receptors (PRRs), including microbicidal peptide human neutrophil α-defensins (HNP) and dermcidin, can exert immunomodulating activity in innate immunity and skin inflammation. We investigated the plasma concentration of HNP and dermcidin, the expression of bacterial toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD)-like receptors of basophils and plasma concentration and ex vivo induction of AD-related inflammatory cytokines and chemokines using ELISA and flow cytometry, in AD patients and control subjects. Plasma concentrations of HNP, dermcidin and AD-related Th2 chemokines CCL17, CCL22 and CCL27 were significantly elevated in AD patients compared with controls (all p < 0.05). Plasma concentrations of CCL27 and CCL22 were found to correlate positively with SCORing atopic dermatitis (SCORAD), objective SCORAD, % area affected, lichenification and disease intensity, and CCL27 also correlated positively with pruritus in AD patients (all p < 0.05). Protein expressions of NOD2 but not TLR2 of basophils were significantly down-regulated in AD patients compared with controls (p = 0.001). Correspondingly, there were lower ex vivo % inductions of allergic inflammatory tumor necrosis factor-α, IL-6 and CXCL8 from peripheral blood mononuclear cells upon NOD2 ligand S. aureus derived muramyl dipeptide stimulation in AD patients comparing with controls. The aberrant activation of bacterial PRRs of basophils and anti-bacterial innate immune response should be related with the allergic inflammation of AD.

Levels of immunoglobulin E specific to the major food allergen and chemokine (C-C motif) ligand (CCL)17/thymus and activation regulated chemokine and CCL22/macrophage-derived chemokine in infantile atopic dermatitis on Ishigaki Island.

Atopic dermatitis (AD) is a multifactorial T-helper (Th)2-mediated skin disease frequently associated with elevated serum immunoglobulin (Ig)E and food allergy is also a Th2- and IgE-mediated adverse immunological reaction. Our previous study indicated the relation of egg allergy history and disease severity of AD. Thus, the purpose of the study was to investigate the levels of IgE specific to major food allergens (egg, milk, wheat) and Th2 chemokines (chemokine [C-C motif] ligand [CCL]17/thymus and activation regulated chemokine [TARC] and CCL22/macrophage-derived chemokine [MDC]) and the relationship between them. A total of 743 nursery school children were enrolled. Dermatologist-based physical examination and a questionnaire survey were also conducted. Significantly increased levels of disease severity markers (CCL17/TARC and CCL22/MDC) were confirmed in children with AD. The levels of CCL22/MDC in all of the children were markedly high compared with those reported in adults. IgE specific to egg white, ovomucoid, wheat and mite antigen were significantly higher in the AD group than in the non-AD group. Among them, IgE specific to egg allergens were well associated with disease severity markers, and IgE specific to ovomucoid seemed particularly well correlated with the presence of egg allergy history. In conclusion, the markedly high level of CCL22/MDC in children as compared with those reported in adults may partly explain the AD-prone nature of children and their spontaneous remission afterwards. Mild but significant correlation of IgE specific to egg allergens and Th2 chemokines may explain correlation of disease severity and comorbidity of egg allergy in our previous study.

Circulating levels of Th1 and Th2 chemokines in patients with ankylosing spondylitis.

OBJECTIVE: Although chemokines are critical elements for the selective attraction and activation of various leukocyte subsets in the inflammatory process, there are few findings concerning T helper (Th) 1 or Th2 chemokines in ankylosing spondylitis (AS). This study was designed to determine whether serum levels of chemokines that are preferentially chemotactic for Th1 (IFN-gamma-inducible protein-10, IP-10/CXCL10) and Th2 (thymus and activation regulated chemokine, TARC/CCL17) and (macrophage derived chemokine, MDC/CCL22) cells were elevated and whether they correlated with the clinical features in patients with AS. METHODS: Forty-two patients with axial AS and 25 healthy controls were enrolled into the study. Serum levels of chemokines (IP-10, TARC and MDC) and cytokines (IFN-γ, TNF-α and IL-4) were examined using ELISA. The disease activity was evaluated by Ankylosing Spondylitis Disease Activity Score (ASDAS). Serum levels of IgG, IgA, IgM, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured. RESULTS: Serum chemokine levels of IP-10, TARC and MDC were significantly higher in patients with AS than those in healthy controls. Serum cytokine levels of IFN-γ, TNF-α were also significantly increased, but the levels of IL-4 were not. Furthermore, IP-10 levels in AS patients correlated with ESP, CRP and ASDAS, while the levels of TARC and MDC did not correlate with these clinic indexes. Correlation analysis between the levels of chemokines and cytokines revealed a positive correlation between IP-10 and TNF-α. The levels of both Th1 and Th2 chemokines decreased under blockade of TNF-α. CONCLUSION: Our results suggest that both a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, cooperatively play a role in the development of AS.