Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system (PNS). A small number of CIDP patients harbors autoantibodies against nodal/paranodal proteins, such as neurofascin 155 (NF155), contactin 1, and contactin-associated protein 1. In most cases, the predominant immunoglobulin (IgG) subclass is IgG4. Node/paranode antibody-positive CIDP demonstrates distinct features compared with antibody-negative CIDP, including a poor response to intravenous immunoglobulin. The neuropathology of biopsied sural nerve shows Schwann cell terminal loop detachment from axons without macrophage infiltration or inflammation. This is partly attributable to IgG4, which blocks protein-protein interactions without inducing inflammation. Anti-NF155 antibody-positive (NF155⁺) CIDP is unique because of the high frequency of subclinical demyelinating lesions in the central nervous system (CNS). This is probably because NF155 coexists in the PNS and CNS. Such cases showing demyelinating lesions in both the CNS and PNS are now termed combined central and peripheral demyelination (CCPD). NF155⁺ CIDP/CCPD commonly presents hypertrophy of spinal nerve roots and cranial nerves, such as trigeminal and oculomotor nerves, and extremely high levels of cerebrospinal fluid (CSF) protein, which indicates nerve root inflammation. In the CSF, the CXCL8/IL8, IL13, TNFα, <em>CCL11</em>/eotaxin, CCL2/MCP1, and IFNγ levels are significantly higher and the IL1β, IL1ra, and GCSF levels are significantly lower in NF155⁺ CIDP than in non-inflammatory neurological diseases. Even compared with anti-NF155 antibody-negative (NF155^-) CIDP, the CXCL8/IL8 and IL13 levels are significantly higher and the IL1β and IL1ra levels are significantly lower than those in NF155⁺ CIDP. Canonical discriminant analysis revealed NF155⁺ and NF155^- CIDP to be separable with IL4, IL10, and IL13, the three most significant discriminators, all of which are required for IgG4 class switching. Therefore, upregulation of both Th2 and Th1 cytokines and downregulation of macrophage-related cytokines are characteristic of NF155⁺ CIDP, which explains spinal root inflammation and the lack of macrophage infiltration in the sural nerves. All Japanese patients with NF155⁺ CIDP/CCPD have one of two specific human leukocyte antigen (HLA) haplotypes, which results in a significantly higher prevalence of <i>HLA-DRB1</i> ^* <i>15:01-DQB1</i> ^* <i>06:02</i> compared with healthy Japanese controls. This indicates an involvement of specific HLA class II molecules and relevant T cells in addition to IgG4 anti-NF155 antibodies in the mechanism underlying IgG4 NF155⁺ CIDP/CCPD.

Keywords: IgG4; chronic inflammatory demyelinating polyneuropathy; combined central and peripheral demyelination; neurofascin 155; node of Ranvier.

Ulcerative colitis (UC) is a complex inflammatory bowel disorder that can induce colonic and rectal dysfunction. Mesalazine, a first-line medicine, is routinely prescribed for UC treatment. However, the pharmacological targets of mesalazine against UC are not detailed in current publications. In the current study, a transcriptomics strategy was applied to reveal the therapeutic targets and molecular mechanisms of mesalazine for treating dextran sulfate sodium (DSS)-induced UC in mice. Compared with the UC group, a total of 1,663 differentially expressed genes were identified in mesalazine-treated mice, of which 262 were upregulated and 1,401 were downregulated. GO and KEGG enrichment analyses indicated that the protective actions of mesalazine for treating UC were related to the functional regulation of immune inflammatory response, such as the regulation of T cells, white blood cells, and cytokine receptor pathways. In addition, ingenuity pathway analysis of the gene network further revealed the inhibitory action of mesalazine on C-C motif chemokine ligands (CCL11 and CCL21) and C-X-C motif chemokine ligands (CXCL3 and CXCR2). Taken together, the current transcriptomic findings revealed anti-UC pharmacological targets, including the newly discovered biotargets CCL11, CCL21, CXCL3, and CXCR2, of mesalazine against DSS-induced intestinal inflammation.

Keywords: differentially expressed genes; mesalazine; pharmacological targets; transcriptomics; ulcerative colitis.

Meibomian gland dysfunction (MGD) has become a prevalent ocular surface disorder. Its pathogenesis is regarded as a self-perpetuating inflammatory vicious circle. Intense Pulsed Light (IPL) treatment was recently applied to improve the meibomian gland function and reduce symptoms of MGD. However, studies investigating the change of specific inflammatory cytokines during IPL treatment remained sparse. To further figure out how IPL treatment modulates the inflammatory cytokines in tears of MGD, we therefore performed a cross-sectional study and enrolled 32 patients from March 2019 to December 2020. The patients received 3 sessions of IPL treatment (10 to 16 J/cm2) at 4-week interval. The signs and symptoms of MGD were evaluated by ocular surface disease index (OSDI), tear film breakup time (TBUT), and meibomian gland yield secretion score (MGYSS). The clinical evaluators and tear samples were analyzed at baseline and at each IPL treatment session. Concentrations of (chemokine ligand) CXCL1, (C-C motif chemokine) CCL11, (tumor necrosis factor) TNF-α, (interferon) IFN-γ, (interleukin) IL-2, IL-6 and (tissue inhibitor of metalloproteinase) TIMP-1were measured by Quantibody Human Dry Eye Disease Array1. OSDI significantly decreased after IPL treatment compared with baseline. TBUT and MGYSS increased consecutively during treatment. CXCL1, CCL11, TNF-α, IFN-γ, IL-2, IL-6 presented significantly decrease and TIMP-1 showed significantly increase from the pretreatment baseline. The changed concentrations of TNF-α, IFN-γ, IL-2, TIMP-1 correlated with TBUT, the changed values of CXCL1, TNF-α, IFN-γ, CCL11, IL-2, IL-6, TIMP-1 correlated with MGYSS, and the changed concentrations of CXCL1, IFN-γ, CCL11, IL-2, IL-6 correlated with TIMP-1. The data supported IPL treatment could significantly relieve both signs and symptoms of MGD. The therapeutic effect of IPL treatment may originate from regulation of inflammatory cytokines including CXCL1, TNF-α, IFN-γ, CCL11, IL-2, IL-6, and TIMP-1.

Essential hypertension (EG) is an age-associated disease. Often EG of elderly patients haven't good way of treatment. Thus, the search of new target molecules for EG therapy is an actual goal of gerontology and molecular medicine. It was shown, that during EG concentrations of GDF11 «youth protein» decreased in 3,3 times and GDF15, JAM-A/1, CCL11 «aging proteins» increased in 1,4-2,4 times. EG patients have abnormal microcirculation processes. It was shown as decreasing in 1,3 and 1,7 times of hemodynamic HI1 and H1-H3 indexes. EG patients have negative correlation of GDF15 concentration with arterial pressure. EG patients have no correlation of JAM-A/1 concentration with arterial pressure. Normal is positive correlation with GDF15, JAM-A/1 concentration with arterial pressure. GDF15 blood level during EG have positive correlation with HI1-HI3 and negative correlation with NEUR_HI2 and MAYER_HI3 indexes. It can show on pathogenesis mechanisms of endothelial and smooth muscles function of vessels tissues. We suppose, that the regulation of GDF11, GDF15, JAM-A/1, CCL11 «youth and aging proteins» can be target object of EG therapy.

OBJECTIVE

To investigate the effects of 18β-glycyrrhetinic acid (GA) on the expression of eotaxin 1 (CCL11), aquaporin protein 1 (AQP1) and eosinophil (EOS) in nasal mucosa of allergic rhinitis (AR) rats.

METHODS

Seventy six Wistar rats were randomly divided into 4 groups, normal control (NC) group, AR model (AR) group, loratadine (LOA) group and 18β-GA group. All the mice in AR, LOA and 18β-GA groups were sensitized intraperitoneally with OVA and AL(OH), from day 1-14, then induced by intranasal administration with OVA from day 14-21, while the mice in NC group were sensitized with saline. The mice in both LOA and 18β-GA group were given LOA and 18β-GA once a day respectively from the 21 d, while the mice in AR and NC groups were administrated with saline. At the end of 1 week, 2 weeks and 3 weeks, the behavioral changes of mice were observed and recorded, the level of CCL11 mRNA was measured by RT-QPCR, and AQP1 expression was investiaged by SP staing. EOS in nasal mucosa was studied with the methods of HE staining.

RESULTS

Compared with NC group, AR group showed typical AR symptoms. With the treatments, AR symptom scores and the expression levels of CCL11, AQP1 and EOS in nasal mucosa were improved significantly (P<0. 05). When compared with AR group, the above statistics in LOA group were down-regulated evidently at different points in time (P<. 05). At the end of 1 week, the above detection results in 18β-GA group were lower than those in AR group (P<0. 05). At the end of 2 weeks, those parameters approached to the levels of LOA and NC group significantly.

CONCLUSIONS

18β-GA administration could down-regulate the expression levels of CCL11, AQP1 and EOS in nasal mucosa of allergic rhinitis rats and cast effects on inhibiting the progress of AR.

Infiltrating myeloid cells in pregnant uteri play critical roles in the establishment of the placenta and maintenance of normal pregnancies. Their recruitment and proliferation are primarily mediated by the interactions of cytokines and chemokines secreted locally with their corresponding receptors. Heme oxygenase-1 (HO-1) has various physiologic properties that contribute to placental vascular development, with deficiencies in HO-1 associated with pregnancy disorders. Here, we investigated the effect of HO-1 on myeloid cell infiltration into pregnant uteri using a partial HO-1-deficient (Het, HO-1+/-) mouse model. With the use of flow cytometry, HO-1 was found predominantly expressed in circulating and uterine myeloid cells, specifically neutrophils and monocytes/macrophages. In pregnant Het uteri, the numbers of neutrophils and monocytes/macrophages were significantly reduced compared with pregnant wild-type (WT; HO-1+/+) uteri. With the use of BrdU in vivo assays, HO-1 deficiency did not affect cell proliferation or blood cell populations. With the use of PCR arrays, gene expression of cytokines (Csf1, Csf3), chemokines (Ccl1, Ccl2, Ccl6, Ccl8, Ccl11, Ccl12, Cxcl4, Cxcl9, Cxcl12), and their receptors (Ccr1, Ccr2, Ccr3, Ccr5) were also reduced significantly in Het compared with pregnant WT uteri. Moreover, with the use of flow cytometry, myeloid CSF1R and CCR2 expression in blood and uteri from both pregnant and nonpregnant mice was characterized, and a deficiency in HO-1 significantly reduced CCR2 expression in infiltrating uterine monocytes/macrophages and dendritic cells (DCs). These data reveal that HO-1 regulates not only cytokine/chemokine production in pregnant uteri but also myeloid cell receptor numbers, suggesting a role of HO-1 in the recruitment and maintenance of myeloid cells in pregnant uteri and subsequent effects on placental vascular formation.

The bronchial epithelium is a very important factor during the inflammatory response, it produces many key regulators involved in the pathophysiology of asthma and COPD. Local influx of eosinophils, basophils, Th2 lymphocytes and macrophages is the source of many cytotoxic proteins, cytokines and other mediators of inflammation. These cells are attracted by eotaxins (eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26). Inhibitors of phosphodiesterase 4 (PDE4) are new anti-inflammatory drugs which cause cAMP accumulation in the cell and inhibit numerous stages of allergic inflammation. The aim of our study was to evaluate the influence of PDE4 inhibitors: rolipram and RO-20-1724 on the expression of eotaxins in human primary bronchial epithelial cells. Cells were preincubated with PDE4 inhibitors for 1 hour and then stimulated with IL-4 or IL-13 alone or in combination with TNF-α. After 48 hours, eotaxin protein level was measured by ELISA and mRNA level by real time PCR. These cells produce CCL24 and CCL26. PDE4 inhibitors increased CCL24 and CCL26 mRNA level irrespectively of the used stimulators. Rolipram and RO-20-1724 had no effect on eotaxin protein production in our experimental conditions. Thus PDE4 inhibitors have no effect on eotaxin protein expression in human primary bronchial epithelial cells. In vitro experiments should be performed using a primary cell model rather than immortalized lines.

Objectives: To characterize the expression profiles of two nuclear-encoded mitochondrial genes previously associated with chronic pain, the translocator protein (TSPO) and family with sequence similarity 173B (FAM173B), in different knee compartments from patients with painful knee OA. Also, to examine their association with the joint expression of inflammatory cytokines/chemokines and clinical symptoms.

Methods: The study was performed on 40 knee OA patients and 19 postmortem (PM) controls from which we collected the knee tissues: articular cartilage (AC), synovial membrane (SM) and subchondral bone (SB). Quantitative real-time polymerase chain reaction was used to determine the relative mRNA levels of TSPO, FAM173B, and inflammatory mediators IL6, IL8, IL10, IL12, MCP1, CCL11 and CCL17. OA patients rated their pain intensity (visual analogue scale), severity of knee-related outcomes (KOOS) and pain sensitivity assessed by pressure algometry.

Results: The gene expression of TSPO in SM was elevated in OA patients compared with control subjects while there were no group differences in AC and SB. Expression of FAM173B was reduced in SM but elevated in SB in OA patients compared with controls. The expression of TSPO and FAM173B in SM and SB was associated with the expression of inflammatory substances, but not in AC. Synovial expression of TSPO correlated with lower pain intensity and FAM173B with increased pressure pain sensitivity in OA.

Conclusion: Our results suggest that altered expression of TSPO and FAM173B is associated with joint expression of inflammatory mediators and with clinical symptoms indicating the relevance for the pathophysiology of knee OA.

Keywords: family with sequence similarity 173B (FAM173B); joint pain; mitochondrial dysfunction; osteoarthritis (OA); synovial inflammation; translocator protein (TSPO).

Our aim was to analyze the relationship between plasma inflammatory biomarkers and CD4+ T-cells evolution in human immunodeficiency virus (HIV) elite controllers (HIV-ECs) with a suppressed viremia. We carried out a retrospective study in 30 HIV-ECs classified into two groups: those showing no significant loss of CD4+ T-cells during the observation period (stable CD4+, n = 19) and those showing a significant decrease of CD4+ T-cells (decline CD4+, n = 11). Baseline plasma biomarkers were measured using a multiplex immunoassay: sTNF-R1, TRAIL, sFas (APO), sFasL, TNF-α, TNF-β, IL-8, IL-18, IL-6, IL-10, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, SDF1α, GRO-α, and CCL11. Baseline levels of sTNF-R1 and CCL11 and sTNF-R1/TNF-α ratio correlated with the slope of CD4+ T-cells (cells/μl/year) during follow-up [r = -0.370 (p = 0.043), r = -0.314 (p = 0.091), and r = -0.381 (p = 0.038); respectively]. HIV-ECs with declining CD4+ T-cells had higher baseline plasma levels of sTNF-R1 [1,500.7 (555.7; 2,060.7) pg/ml vs. 450.8 (227.9; 1,263.9) pg/ml; p = 0.018] and CCL11 [29.8 (23.5; 54.9) vs. 19.2 (17.8; 29.9) pg/ml; p = 0.041], and sTNF-R1/TNF-α ratio [84.7 (33.2; 124.2) vs. 25.9 (16.3; 75.1); p = 0.012] than HIV-1 ECs with stable CD4+ T-cells. The area under the receiver operating characteristic (ROC) curve [area under ROC curve (AUROC)] were 0.758 ± 0.093 (sTNF-R1), 0.727 ± 0.096 (CCL11), and 0.777 ± 0.087 (sTNF-R1/TNF-α). The cut-off of 75th percentile (high values) for these biomarkers had 71.4% positive predictive value and 73.9% negative predictive value for anticipating the evolution of CD4+ T-cells. In conclusion, the loss of CD4+ T-cells in HIV-ECs was associated with higher levels of two plasma inflammatory biomarkers (sTNF-R1 and CCL11), which were also reasonably accurate for the prediction of the CD4+ T-cells loss.

Context: In nonallergic (naive) mice, type I cysteinyl-leukotriene receptors (CysLT₁R) mediate the stimulatory effects of cytokines (eotaxin/CCL11, interleukin[IL] - 13), and nonsteroidal anti-inflammatory drugs (NSAID; indomethacin, aspirin) on eosinophil production by IL-5-stimulated bone-marrow. In ovalbumin (OVA)-sensitized mice, airway challenge-induced bone-marrow eosinophilia and eosinopoiesis are prevented by pretreatment with blockers of adrenal glucocorticoid signaling (RU486, metyrapone) or cysteinyl-leukotriene (CysLT) signaling (montelukast).Objective: To define whether allergen challenge modifies subsequent bone-marrow responses to CysLT, NSAID, and cytokines which act through type 1 CysLT receptor (CysLT₁R).Methods: We examined the effects of sensitization/challenge, and of in vivo blockade of endogenous glucocorticoid or CysLT signaling, on ex vivo responses to CysLT1R-dependent stimuli.Results and discussion: Challenge abolished the stimulatory ex vivo responses to CysLT₁R-dependent agents in the eosinophil lineage. In cultured bone-marrow of naive, sensitized and sensitized/challenged mice, responses to leukotriene D₄ (LTD₄) in eosinophil differentiation ex vivo shifted from stimulatory (without challenge) to suppressive (following challenge). Both stimulatory and suppressive LTD₄ effects were blocked by montelukast. The suppressive LTD₄ effect was accounted for by accelerated maturation followed by apoptosis of eosinophils. RU486/metyrapone or montelukast pretreatments before challenge prevented the challenge-induced change in subsequent responses to all these agents. Hence, allergen challenge has two separate effects on bone-marrow: (a) it enhances eosinopoiesis in vivo and upregulates ex vivo responses to IL-5; (b) it promotes a faster, but self-limiting, response to LTD₄ and CysLT1R-dependent stimuli.Conclusion: Allergen challenge modifies eosinopoiesis through systemic (glucocorticoid- and CysLT1R-dependent) mechanisms, increasing responses to IL-5 but restricting responses to subsequent CysLT1R stimulation.

Objective: We sought to explore the relationships between multiple chemokines with spirometry, inflammatory mediators and CT findings of emphysema, small airways disease and bronchial wall thickness.

Methods: All patients with COPD (n = 65) and healthy control subjects (n = 23) underwent high-resolution CT, with image analysis determining the low attenuation area (LAA), ratio of mean lung attenuation on expiratory and inspiratory scans (E/I MLD) and bronchial wall thickness of inner perimeter of a 10-mm diameter airway (Pi10). At enrollment, subjects underwent pulmonary function studies, chemokines and inflammatory mediators measurements.

Results: Multiple chemokines (CCL2, CCL3, CCL5, CX3CL1, CXCL8, CXCL9, CXCL10, CXCL11 and CXCL12) and inflammatory mediators (MMP-9, MMP-12, IL-18 and neutrophil count) were markedly increased in the serum of COPD patients compared with healthy controls. There were associations between small airway disease (E/I MLD) and CCL11, CXCL8, CXCL10, CXCL11, CXCL12 and CX3CL1. Especially CXCL8 and CX3CL1 are strongly associated with E/I MLD (r = 0.74, p < 0.001; r = 0.76, p < 0.001, respectively). CXCL8, CXCL12 and CX3CL1 were moderately positively correlated with emphysema (%LAA) (r = 0.49, p < 0.05; r = 0.51, p < 0.05; r = 0.54, p < 0.01, respectively). Bronchial wall thickness (Pi10）showed no significant differences between the COPD and healthy controls,，but there was an association between Pi10 and FEV₁% in COPD patients (r=-0.420, p = 0.048). Our statistical results showed that there were not any associations between airway wall thickness (Pi10) and chemokines.

Conclusion: Pulmonary chemokines levels are closely associated with the extent of gas trapping, small airways disease and emphysema identified on high-resolution chest CT scan.

Advances in knowledge: This study combines quantitative CT analysis with multiplex chemokines and inflammatory mediators to identify a new role of pathological changes in COPD.

Introduction: Solitary juvenile polyps (JP) are characterized by a benign disease course with low recurrence rate but present with signs of intestinal inflammation. To better understand the underlying pathogenesis, we performed histological and molecular evaluation targeting distinct immune mechanisms.

Methods: Pediatric patients with JP (n = 12), with treatment-naïve inflammatory bowel disease (IBD; [n = 41]) as inflammatory control, and non-IBD controls (n = 14) were investigated. For a comparative analysis of infiltrating immune cells, a next-generation tissue microarray of biopsies was assembled, immunostained, and scored. Targeted transcriptional profiling was performed using a customized immunology panel.

Results: In JP, a predominant accumulation of neutrophils and eosinophils was observed. RNA expression profiles revealed increased levels of CXCL8, CXCL5, and CCL11 transcripts in JP, indicating an enhanced recruitment of neutrophils and eosinophils. Moreover, messenger RNA levels of the proinflammatory cytokine IL1b and the inflammation-amplifying receptor TREM1 were higher in JP, whereas we could not find signs of a functionally polarized Tcell response in JP when compared with IBD.

Discussion: Patients with JP and patients with treatment-naïve IBD have distinct cell infiltrates during active disease. The ample presence of eosinophils in JP supports neutrophil accumulation, which is responsible for the elevated release of calprotectin. Intriguingly, however, we were not able to identify a functionally polarized T-cell response in JP, which indicates that during the acute onset of inflammation in JP, a potent adaptive immune memory is not established. This may explain the low reoccurrence rate of JP.

OBJECTIVE

To investigate the distribution of mast cells in nasal polyps.

METHODS

Biopsy specimens from patients with nasal polyps (n = 20) and control patients (n = 8) were obtained and included in this study. The distribution of mast cells in nasal polyps and the expression of chemokines (CCL5, CCL11, CX3CL1, IL-8, IL-6) in the epithelial cells of normal nasal mucosa and nasal polyps was determined by immunohistochemistry.

RESULTS

Mast cells migrate to intraepithelial in nasal polyps and the expression of chemokines (CCL5, CCL11, CX3CL1, IL-8) was up regulated in the epithelial cells of nasal polyps compare to normal nasal mucosa.

CONCLUSIONS

Our findings showed that mast cells migrate to intraepithelial in nasal polyps and the over expression of chemotaxins (CCL5, CCL11, CX3CL1, IL-8) may be response for mast cells' migration in nasal polyps. Mast cells might be associated with the development of nasal polyps.

Recent studies have shown that mast cells are involved in pathophysiologic processes of chronic inflammation. However, little is known about the distribution of mast cells in nasal polyps, which is a chronic inflammatory disease of the upper airways. Biopsy specimens from patients with nasal polyps (n = 20) and control patients without nasal polyps (n = 8) were included in this study. The distribution of mast cells in nasal polyps was determined by immunohistochemistry. Meanwhile, we detected the expression of chemokines (CCL5, CCL11, CX3CL1, IL-8, IL-6) in the epithelial cells of normal nasal mucosa and nasal polyps. In addition, the expression of these chemokines was investigated by western bolting in airway epithelial cells line (A549 cells) under inflammatory condition. Mast cells migrated toward intraepithelium in nasal polyps and the expression of chemokines (CCL5, CCL11, CX3CL1, IL-8) was up-regulated in the epithelial cells of nasal polyps compared with normal nasal mucosa. The expression of chemokines was also up-regulated in A549 cells after Lipopolysaccharide (LPS)-treatment for 3 hr and 6 hr. Our findings showed that mast cells migrate toward intraepithelium in nasal polyps and the overexpression of chemokines (CCL5, CCL11, CX3CL1, IL-8) suggested that they might be responsible for mast cells migration. It implies that mast cell play potential roles in the development of nasal polyps.

AP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation-dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFNγ, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2-associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response.

Around one third of schizophrenia patients are non-responders to antipsychotic therapy. The present study aimed to delineate the pathway-phenotypes of non-remitters (NRTT) and partial remitters (PRTT) to treatment with antipsychotics as defined using the Global Clinical Impression scales. We recruited 60 NRTT, 50 PRTT and 43 healthy controls and measured schizophrenia symptoms, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and μ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Soft independent modeling of class analogy (SIMCA) showed that NRTT and PRTT are significantly discriminated with a cross-validated accuracy of 94.7% and are qualitatively distinct classes using symptomatome, and neuro-immune-opioid-cognitome (NIOC) features as modeling variables. Moreover, a NIOC pathway phenotype discriminated PRTT from healthy controls with an accuracy of 100% indicating that PRTT and controls are two qualitative distinct classes. Using NIOC features as discriminatory variables in SIMCA showed that all PRTT were rejected as belonging to the normal control class and authenticated as belonging to their target class. In conclusion, a non-response to treatment can best be profiled using a SIMCA model constructed using symptomatome and NIOC features. A partial response should be delineated using SIMCA by authenticating patients as controls or PRTT instead of using scale-derived cut-off values or a number of scale items being rated mild or better. The results show that PRTT is characterized by an active NIOC pathway phenotype and that both NRTT and PRTT should be treated by targeting neuro-immune and opioid pathways.

Keywords: Biomarkers; Fatigue and physiosomatic symptoms; Inflammation; Major depression; Neuroimmunomodulation; Schizophrenia.

Aim: We aimed to discover whether group 2 innate lymphoid cells (ILC2s) and cytokines in nasal lavage fluid could be used to predict eosinophilic infiltration in mice with eosinophilic chronic rhinosinusitis (ECRS).

Methods: Ten mice were divided into two groups. The ECRS group received an intranasal challenge of Aspergillus oryzae protease (AP) and ovalbumin (OVA) to establish disease. A control group received intranasal phosphate-buffered saline. Histopathology of nasal cavities and paranasal sinuses, and cytokine and ILC2s levels in nasal lavage fluid were analyzed and compared between the ECRS and control mouse groups.

Key findings: ILC2s numbers were not significantly higher in the nasal lavage fluid of the ECRS group mice compared with those of the control group. Eotaxin/chemokine (CC motif) ligand 11 (CCL11) levels were significantly higher in the nasal lavage fluid of mice in the ECRS group compared with those in the control group. However, no statistical differences were seen in the classic proinflammatory cytokines, IL-33, IL-25, and thymic stromal thymopoietin (TSLP), or the classic type 2 cytokines, IL-4, IL-5, and IL-13 between groups.

Significance: Eotaxin/CCL11 levels in nasal lavage fluid rather than that of ILC2s and classic proinflammatory and type 2 cytokines were significantly higher in ECRS mice compared with control ones. Eotaxin/CCL11 showed diagnostic and therapeutic value; however, more studies are needed to test and verify its value.

Keywords: Airway disease; Cytokines; Eosinophils; ILC2s; Mouse.

Mitral stenosis (MS) is a consequence of rheumatic heart disease that leads to heart failure requiring mechanical intervention. Percutaneous mitral commissurotomy (PMC) is the treatment of choice for the intervention, and currently there are no soluble markers associated with hemodynamic improvement after PMC. This study aims to determine the changes in cytokine/chemokine plasma levels, as well as T cell activation after PMC, and to investigate their association with immediate hemodynamic improvement and clinical outcomes. Plasma samples from eighteen patients with well-defined MS who underwent PMC and 12 healthy controls were analyzed using BioPlex immunoassay. We observed that 16 out of the 27 (60%) molecules assessed were altered in patients' plasma pre-PMC as compared to control group. Of those, IL-1β, IL-12, IL-6, IL-4, PDGF, and CCL11 showed significant decrease after PMC. Stratifying the patients according to adverse outcome after a 28-month median follow up, we detected a significant reduction of IL-1β, IL-12, IL-6, IL-4, IFN-γ, CXCL-10, VEGF, FGF and PDGF post-PMC in patients without events, but not in those who presented adverse events during the follow-up. Patients with adverse outcomes had lower IL-10 pre-PMC, as compared to the ones without adverse events. In addition, the frequency of CD8+ activated memory cells was increased after PMC, while the frequency of CD4+ activated memory cells did not change. Our results show an association between the decrease of specific cytokines and changes in T cell activation with hemodynamic improvement post-PMC, as well as with long-term outcomes, suggesting their possible use as soluble markers for hemodynamic recovery after MS intervention.

Keywords: T cells; cytokines; mitral stenosis; percutaneous mitral commissurotomy; rheumatic heart disease.

We have cloned and performed the first functional characterization of the chemokine receptor, CCR3, of Cynomolgus monkey (Macaca fascicularis). The deduced amino acid sequence of the cloned Cynomolgus CCR3 was found to be more similar to that of a previously-reported Rhesus (Macaca mulatta) CCR3 (99.4%) than that of a reported Cynomolgus CCR3 (98.0%). Stably-transfected Cynomolgus CCR3 bound human eotaxin (CCL11) with similar kinetics (Kd 240 pM) and was responsive to human CCR3 ligands (eotaxin [CCL11], eotaxin-2 [CCL24], and MCP4 [CCL13]) in Ca(2+) mobilization and chemotaxis assays, thus provides a useful alternative species model system for the analysis of modulators of eotaxin--CCR3 induced signaling and activation.

Petroleum crude oil spills are common and vary in size and scope. Spill response workers throughout the course of remediation are exposed to so-called weathered oil and are known to report diverse health effects, including contact dermatitis. A murine model of repeated exposure to weathered marine crude oil was employed utilizing two strains of mice, C57BL/6 and BALB/c, to investigate the pathology of this irritant and identify the principal hydrocarbon components deposited in skin. Histopathology demonstrated clear signs of irritation in oil-exposed skin from both mouse strains, characterized by prominent epidermal hyperplasia (acanthosis). BALB/c mice exposed to oil demonstrated more pronounced irritation compared with C57BL/6 mice, which was characterized by increased acanthosis as well as increased inflammatory cytokine/chemokine protein expression of IL-1β, IL-6, CXCL10, CCL2, CCL3, CCL4, and CCL11. A gas chromatography/mass spectrometry method was developed for the identification and quantification of 42 aliphatic and EPA priority aromatic hydrocarbons from full thickness skin samples of C57BL/6 and BALB/c mice exposed to oil samples. Aromatic hydrocarbons were not detected in skin; however, aliphatic hydrocarbons in skin tended to accumulate with carbon numbers greater than C16. These preliminary data and observations suggest that weathered crude oil is a skin irritant and this may be related to specific hydrocarbon components, although immune phenotype appears to impact skin response as well.

Keywords: Petroleum; dermatitis; inflammation; irritant; oil spill; skin.

Objective: The contributions of intervertebral disc disease and subject-specific covariates to systemic inflammation in low back pain are unknown. We examined the effects of symptomatic disc herniation (DH) and MRI herniation severity on serum cytokine levels in clinical subjects.

Design: Cytokine levels from lumbar DH subjects (N=78) were compared to control subjects (N=57) accounting for effects of DH, age, BMI and gender. Effect of DH severity on cytokine levels was analyzed on subsets of subjects with acute or chronic pain. Serum cytokines were also analyzed in a subset of patients between pre- and 3 months post-surgery.

Results: Cytokine levels were elevated in the serum of patients with symptomatic DH, and the covariates age, BMI and gender significantly contributed to levels of some cytokines. Severity of herniation was a significant contributor to pain intensity (VAS), serum levels of HMGB1, PDGFbb, and IL-9. The relationship between DH severity and cytokine levels was confirmed in subjects with chronic, but not acute symptoms. Serum levels of MIF decreased, whereas levels of CCL3, CCL11, CXCL1, and CXCL10 were significantly elevated post surgery.

Conclusions: This study is the first to show that DH severity is coordinately associated with changes in serum levels of inflammatory cytokines in chronic pain subjects. HMGB1, PDGFbb and IL-9 are novel mediators of increasing DH severity, indicative of cellular damage, neuro-inflammation and angiogenesis. Resolution of inflammation was observed with decrease in MIF post surgery. However, elevated chemokine levels indicate ongoing remodeling and wound healing at 3-month time point.

Keywords: Intervertebral disc; MRI severity; herniated disc; inflammation; pain.

Background: In the pathogenesis of intermittent allergic rhinitis (IAR), the inflammatory reaction is of importance. CD48, belonging to the CD2 family, participates in mast cell-stimulating cross-talk, facilitates the formation of the mast cell/eosinophil effector unit, and is expressed by eosinophils.

Objectives: To assess the serum level of soluble form of CD48 (sCD48) in patients with IAR during and out of the pollen season and correlate with the disease severity and with eosinophil-related parameters.

Materials and methods: Sixty-three patients (female: 79%; mean age: 30.58) were included to the study. Forty-five patients were assessed during the pollen season and other 42 patients during out of the pollen season. Twenty-four patients (female: 37.50%; mean age: 27.90) were evaluated twice, during the pollen season and out of the pollen season. sCD48, ECP, eotaxin-1/CCL11 serum levels together with complete blood count, and fractional exhaled nitric oxide bronchial and nasal fraction (FeNO) were performed. The severity of symptoms was assessed using the Total Nasal Symptom Score (TNSS), and neutrophil-to-lymphocyte (NLR) and eosinophil-to-lymphocyte (ELR) ratios were calculated.

Results: sCD48 serum level, FeNO nasal and bronchial fractions, and TNSS were significantly higher in the IAR group in the pollen season compared with out of the pollen season. Differences in ECP, eotaxin-1/CCL11 serum levels, and NLR and ELR were not significant between season and out of the season. No correlations were found between sCD48 and eosinophil-related parameters.

Conclusions: sCD48 may be a biomarker to the exacerbation phase in patients with IAR. One can assume that CD48 participates in the pathogenesis of IAR.

Keywords: Allergic rhinitis; CD48; Fractional exhaled nitric oxide; Intermittent allergic rhinitis; Nitric oxide.