Increased infiltration of immune cell subsets and altered soluble factor profile in aqueous humor of glaucoma patients correlates with disease severity
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Infiltration (HVAC)
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Immunophenotyping
Monocyte
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There is a critical need to deconvolute the heterogeneity displayed by the minor salivary glands of primary Sjögren's syndrome (pSS) patients. This is challenging primarily because the disease etiology remains unknown. The hypothesis includes that initial events in the disease pathogenesis target the salivary glands, thereby triggering the development of focal infiltrates (≥50 mononuclear cells) and finally germinal center-like structures. However, the proportion of key mononuclear immune cells residing at these sites, in combination with the overall ratio of morphometric tissue atrophy and adipose infiltration within the minor salivary glands (MSG) parenchyma at distinct phases of inflammatory disease establishment and progression have not been quantified in detail. In this cross-sectional study, we intended to address this problem by stratifying 85 patients into mild (S1), moderate (S2), and severe (S3) stages using the Inflammatory severity index. We found that mild (<3%) and marked (≥3%) levels of atrophy were accompanied by the respective levels of adipose infiltration in the non-SS sicca controls (p <0.01), but not in pSS patients. The percentage of adipose infiltration significantly correlated with the age of patients (r = 0.458, p <0.0001) and controls (r = 0.515, p <0.0001). The CD4+ T helper cell incidence was reduced in the focal infiltrates of the MSG of S2 patients compared to S1 (p <0.01), and in S2 compared to S1 and S3 combined (p <0.05). CD20+ B cells increased from S1 to S3 (p <0.01) and S2 to S3 (p <0.01), meanwhile CD138+ plasma cells diminished in S3 patients compared to both S1 and S2 groups combined (p <0.01). The proportion of patients with anti-Ro/SSA+, anti-La/SSB+, and RF+ increased over the course of inflammatory disease progression and they were significantly more common in the S3 group relative to S1 (p <0.05). On the other hand, S2 patients measured a higher mean salivary flow relative to S1 and S3 patients combined (p <0.05). Our results demonstrate how the proposed Inflammatory severity index stratification revealed pathological cell and tissue-associated aberrations in the salivary component over the course of inflammatory progression, and their correlations to clinical outcomes. This could be directly transferred to the optimization of available diagnostic strategies applied for pSS patients.
Mononuclear cell infiltration
Pathogenesis
Infiltration (HVAC)
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Psoriasis is a chronic immune-mediated skin disease accompanied by systemic inflammation and comorbidities. We analyzed peripheral blood mononuclear cells (PBMCs) in the search for immune signatures and biomarkers related to psoriasis severity and treatment effect. Thirty-two patients with psoriasis and 10 matched healthy controls were included. PBMCs were collected before and after initiation of anti-TNF, anti-IL-17 or anti-IL-12/23 treatment and analyzed utilizing 26-parameter mass cytometry. The number of circulating Th17, Th22, Th9, and cytotoxic T cells were increased in severe psoriasis. Intracellular pp38 and pERK in T helper cells were associated with disease severity. Differences between responders and nonresponders regarding cell composition and intracellular signaling were identifiable already at inclusion. Biological treatment induced memory cells, restored inhibitory PD-1 function of T cells, and reduced a potential pro-atherogenic profile in monocytes. In conclusion, these results indicate amelioration of systemic inflammation in psoriasis after biological treatment. Such broad immune profiling may enable prospective stratification of patients regarding future treatment response. Successful early intervention may lead to a healthier trajectory with favorable implications on later comorbidities.
Mass cytometry
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Patients with juvenile idiopathic arthritis often develop chronic anterior uveitis (JIAU). JIAU patients possess a particularly high risk for developing secondary glaucoma when inflammatory inactivity has been achieved. By using multiplex bead assay analysis, we assessed levels of pro- and anti-inflammatory cytokines, chemokines, or metalloproteinases in the aqueous humor (AH) of patients with clinically inactive JIAU with (JIAUwG) or without secondary glaucoma (JIAUwoG), or from patients with senile cataract as controls. Laser-flare photometry analysis prior to surgery showed no significant differences between JIAUwG or JIAUwoG. Compared with the control group, levels of interleukin-8, matrix metalloproteinase-2, -3, -9, serum amyloid A (SAA), transforming growth factor beta-1, -2, -3 (TGFβ-1, -2, -3), and tumor necrosis factor-alpha in the AH were significantly higher in patients with clinically inactive JIAUwG or JIAUwoG. Samples from JIAwoG patients displayed significantly higher levels of SAA (P < 0.0116) than JIAUwG patients. JIAUwG patients showed an increased level of TGFβ-2 in AH samples compared with JIAUwoG (P < 0.0009). These molecules may contribute to the clinical development of glaucoma in patients with JIAU.
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Measurement of optic disc sizeEDITOR,-Garway-Heath et al described a "keratometry and ametropia" method to correct measurements of optic disc size for ocular magnification. 1 The new method implies that the refraction, the power of the lens, and the power of the cornea are all independent (uncorrelated) variables.Table 2 on page 644 (Summary of ocular biometry) clearly demonstrates that this is not always the case; in fact, the variance of the lens power was almost the same as the variance of the total power of the eye.The explanation has to be that the power of the lens and cornea were negatively correlated.Measurements of the corneal curvature were therefore of little use for their purpose.Garway-Heath et al noted that the improvement over the use of uncorrected measurements was moderate, but they failed to draw the obvious conclusion: if correction is necessary, and correction based on spectacle refraction is considered unsatisfactory, correction based on measurements of the axial length of the eye is the only alternative-and quite feasible in these days when ultrasound biometry is used to predict intraocular lens power for cataract surgery.
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Purpose: To investigate which cytokines and chemokines are involved in the immunopathogenesis of acute retinal necrosis (ARN), and whether cytokine profiles are associated with clinical manifestations, such as visual outcome. Methods: Serum and aqueous humor (AH) samples of 19 patients with ARN were analyzed by multiplex immunoassay. Infectious controls consisted of 18 patients with rubella virus–associated Fuchs' uveitis and 20 patients with ocular toxoplasmosis all confirmed by intraocular fluid analyses. The control group consisted of seven paired AH and serum samples from seven noninflammatory control patients with age-related cataract. In each sample, 4 anti-inflammatory, 12 proinflammatory, 2 vascular, and 4 other immune mediators were measured. In addition, various clinical characteristics were assessed. Results: In ARN, 10 of the 22 mediators, including most proinflammatory and vascular mediators such as IL-6, IL-8, IL-18, MIF, MCP-1, Eotaxin, IP-10, IL-15, sICAM-1, and sVCAM-1, were significantly elevated when compared to all controls. In addition, one anti-inflammatory mediator (IL-10) was significantly elevated in ARN as compared to the controls. No association was found between the time of sampling and the extent and levels of immune mediator expression. Conclusions: The pathogenesis of ARN is characterized by the presence of predominantly proinflammatory cytokines and chemokines with high expression levels as compared to other infectious causes of uveitis. There are no indications for an obvious Th-1 or Th-17 pathway. The combined data suggest that immune mediator expression is related to severity of disease, which is more fulminant in ARN, rather than to a specific uveitis entity.
Proinflammatory cytokine
Pathogenesis
Acute retinal necrosis
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Microparticles (MPs) could be considered biomarkers of cell damage and activation as well as novel signalling structures. Since rheumatoid arthritis (RA) is characterized by immune and endothelial activation, the main aim of the present study was to analyse MP counts in RA patients. Citrated-blood samples were obtained from 114 RA patients, 33 healthy controls (HC) and 72 individuals with marked cardiovascular (CV) risk without autoimmune manifestations (CVR). MPs were analysed in platelet-poor plasma (PPP) and different subsets were identified by their surface markers: platelet- (CD41+), endothelial- (CD146+), granulocyte- (CD66+), monocyte- (CD14+) and Tang- (CD3+CD31+) derived. Disease activity score (DAS28), clinical and immunological parameters as well as traditional CV risk factors (diabetes, hypertension, dyslipidaemia and obesity) were registered from clinical records and all data were integrated using Principal Component Analysis (PCA). Absolute MP number was increased in RA patients compared with HC and positively correlated with traditional CV risk factors, similar to that of CVR subjects. In addition, frequency of the different MP subsets was different in RA patients and significantly associated with disease features. Moreover, in vitro assays revealed that MPs isolated from RA patients were able to promote endothelial activation and exhibited detrimental effects on human microvascular endothelial cells (HMEC-I) endothelial cell functionality. Circulating MPs from RA patients displayed quantitative and qualitative alterations that are the result of both disease-specific and traditional CV risk factors. Accordingly, this MP pool exhibited in vitro detrimental effects on endothelial cells, thus supporting their role as biomarkers of vascular damage.
Endothelial Dysfunction
CD31
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Purpose To evaluate the systemic immune-inflammation index (SII) levels, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in patients with dry eye disease (DED) and to compare with control subjects.Methods This prospective study included 47 DED patients and 47 age- and sex-matched healthy controls. Ophthalmological examination, diagnostic DED tests, and routine complete blood cell count parameters were analyzed. The SII value was calculated as follows: platelet count × (neutrophil/lymphocyte).Results The mean SII, NLR, and PLR levels were significantly higher in DED patients compared to controls (p < .001, p < .001 and p = .009, respectively). Using the receiver operating characteristics (ROC) curve analysis to predict patients with DED, the highest area under the curve (AUC) was determined SII (0.761 for SII, 0.727 for NLR, and 0.653 for PLR).Conclusions As a novel tool superior to other inflammatory markers, SII may be a cheap and reliable indicator of inflammatory status in DED patients.
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Most of the cells found in lung parenchyma in patients with idiopathic pulmonary fibrosis are activated T lymphocytes and macrophages. The serum levels of three markers of cell mediated immunity were measured in 20 patients with idiopathic pulmonary fibrosis, in 20 normal subjects and in 12 patients with sarcoidosis to evaluate their clinical and prognostic significance in idiopathic pulmonary fibrosis. The three markers were: soluble CD8 (from activated suppressor-cytotoxic lymphocytes), soluble interleukin (IL)-2 receptors (from activated T cells and macrophages), and neopterin (from activated macrophages). Patients with idiopathic pulmonary fibrosis had higher levels of all three markers than the control subjects. Soluble IL-2 receptor and neopterin tended to be lower (though not significantly) in patients with idiopathic pulmonary fibrosis than in those with sarcoidosis, whereas soluble CD8 was similar in the two groups of patients. No correlation was found between soluble IL-2 receptors or soluble CD8 and the clinical, radiological, and physiological measures of disease activity or with clinical outcome (after a mean follow up of 23 months). Tumour necrosis factor levels were also determined. Only 30% of patients with idiopathic pulmonary fibrosis or sarcoidosis had detectable circulating tumour necrosis factor; these patients had a lower percentage of bronchoalveolar lavage fluid neutrophils in their lavage fluid. Tumour necrosis factor levels did not correlate with clinical measures of severity or outcome. Thus our data support the hypothesis that cell mediated alveolitis occurs in idiopathic pulmonary fibrosis. They do not, however, provide evidence to support the use of these markers of cell mediated immunity to monitor the clinical course in these patients.
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Abstract We aimed to identify differences in cytokine/chemokine levels in the aqueous humor (AH) of primary open-angle glaucoma (POAG) patients who suffered from scarring, compared with POAG patients with no scarring after trabeculectomy surgery. Identification of differently expressed cytokines and chemokines may help to understand scarring and fibrotic processes following trabeculectomy, and to make predictions for the outcome of fistulating surgery in the future. Furthermore, the identification of cell signaling pathways involved in fibrosis offers the opportunity for a more specific antifibrotic therapy with reduced side effects, and an improvement in long-term surgical outcome. Eight samples of AH were collected during trabeculectomy surgery and commercially available cytokine/chemokine arrays were used. Specific, differently expressed proteins (cytokines/chemokines) in AH samples from patients with positive and negative surgery outcomes were detected. These proteins were classified based on their known profibrotic, inflammatory, adhesive, and apoptotic properties. Transforming growth factor β (TGF-β) and vascular endothelial growth factor (VEGF) were among the most important profibrotic cytokines that we detected. Differences in the fold change of protein expression were highly significant between patients after successful and failed trabeculectomy surgery, and these were processed and visualized using ExprEssence software. This pilot study revealed differences in concentrations of cytokines/chemokines in AH between the two examined groups of patients. Our findings suggest that a positive outcome from trabeculectomy is strongly related to an inhibition of the fibrosis process.
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