Peritoneal membrane failure due to fibrosis limits the use of peritoneal dialysis (PD). Peritoneal fibrosis may potentially be induced by sterile inflammation caused by ongoing cellular stress due to prolonged exposure to PD solutions (PDS). Effective therapies to prevent this process remain to be developed. Toll-like receptors (TLRs) mediate sterile inflammation by recognizing damage-associated molecular patterns (DAMPs) released by cellular stress. We evaluated the involvement of TLRs and DAMPs in PDS-induced fibrosis models and the therapeutic potential of TLR-DAMP targeting for preventing fibrosis. A range of PDS elicited pro-inflammatory and fibrotic responses from PD patient peritoneal leukocytes, mesothelial cells and mouse peritoneal leukocytes. TLR2/4 blockade of human peritoneal cells or TLR2/4 knockouts inhibited these effects. PDS did not induce rapid ERK phosphorylation or IκB-α degradation, suggesting that they do not contain components capable of direct TLR activation. However, PDS increased the release of Hsp70 and hyaluronan, both TLR2/4 DAMP ligands, by human and mouse peritoneal cells, and their blockade decreased PDS-driven inflammation. Soluble TLR2, a TLR inhibitor, reduced PDS-induced pro-inflammatory and fibrotic cytokine release ex vivo. Daily catheter infusion of PDS in mice caused peritoneal fibrosis, but co-administration of soluble TLR2 prevented fibrosis, suppressed pro-fibrotic gene expression and pro-inflammatory cytokine production, reduced leukocyte/neutrophil recruitment, recovered Treg cell levels and increased the Treg:Th17 ratio. Thus, TLR2/4, Hsp70 and hyaluronan showed major roles in PDS-induced peritoneal inflammation and fibrosis. The study demonstrates the therapeutic potential of a TLR-DAMP targeting strategy to prevent PDS-induced fibrosis.
Our findings show that in selected adult patients, renal biopsy can be performed as a day-case procedure. Given the benefits of day-case strategies in terms of patient and healthcare costs, we advocate increased utilization of this technique.
The profile of the inflammatory cell infiltrate in chronic hyperplastic candidosis (CHC) was determined in oral mucosal biopsies by immunohistochemistry. One tonsillar tissue section was included as an immunohistochemistry control, whilst squamous papilloma (n = 4) with secondary Candida infection was used as Candida controls. Oral lichen planus tissues (n = 10) provided negative controls for Candida presence, as well as positive controls for inflammation. Immunohistochemistry employed antibodies specific for CD3+ (T lymphocytes), CD4+ (T helper cells), CD8+ (cytotoxic T cells), and CD20+ (B lymphocytes). Manual counting of stained cells from digitised images determined the proportion of each cell type relative to the total number of cells, and these were assessed in the mucosa, the epithelium, and the lamina propria. The mean proportion of CD3+ cells was significantly higher than CD20+ cells in all tissue types. For CHC, the mean proportion of CD3+ cells in entire tissues was 15.6%, with the highest proportion in the lamina propria (32.6%) compared with the epithelium (3.9%). CD20+ cells were in much lower proportions (1.8%) in CHC, with the highest proportion (3.6%) in the lamina propria. T lymphocytes were predominately CD4+ cells (9.0%) compared with CD8+ cells (4.4%). CD4+ cells were most prevalent in the lamina propria (23.1%) compared with the epithelium (mean = 3.2%). From these results, it was concluded that the immune response invoked by Candida in CHC is primarily driven by the T helper cells.
Previous research into the inflammatory cell infiltrate of chronic hyperplastic candidosis (CHC) determined that the immune response is primarily composed of T cells, the majority of which are T helper (CD4+) cells. This present investigation used immunohistochemistry to further delineate the inflammatory cell infiltrate in CHC. Cells profiled were those expressing IL-17A cytokine, EBI3 and IL-12A subunits of the IL-35 cytokine, and FoxP3+ cells. Squamous cell papilloma (with Candida infection) and oral lichen planus tissues served as comparative controls to understand the local immune responses to Candida infection. The results demonstrated that Candida-induced inflammation and immune regulation co-exist in the oral mucosa of CHC and that high prevalence of cells expressing the EBI3 cytokine subunit may play an important role in this regulation. This balance between inflammation and immune tolerance toward invading Candida in the oral mucosa may be critical in determining progress of infection.
Hyaluronan (HA) is a ubiquitous extracellular matrix glycosaminoglycan composed of repeated disaccharide units of alternating D-glucuronic acid and D-N-acetylglucosamine residues linked via alternating β-1,4 and β-1,3 glycosidic bonds. HA is synthesized in humans by HA synthase (HAS) enzymes 1, 2, and 3, which are encoded by the corresponding HAS genes. Previous in vitro studies have shown characteristic changes in HAS expression and increased HA synthesis in response to wounding and proinflammatory cytokines in human peritoneal mesothelial cells. In addition, in vivo models and human peritoneal biopsy samples have provided evidence of changes in HA metabolism in the fibrosis that at present accompanies peritoneal dialysis treatment. This review discusses these published observations and how they might contribute to improvement in peritoneal dialysis.
Chest pain (CP) is a very common presentation with a wide range of differential diagnoses, including life-threatening conditions, which need to be considered, diagnosed and treated urgently. Cardiac CP accounts for less than one-third of causes. Echocardiography is a valuable non-invasive tool that can help in diagnosing and treating patients presenting with CP. National Institute for Health and Care Excellence (NICE), European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines state that echocardiography can help in the diagnosis of acute coronary syndromes and also in ruling out other serious conditions. We present three cases where transthoracic echocardiography (TTE) was essential in assessing patients, making the correct diagnosis and offering the right treatment. This article emphasises the importance of using TTE in assessing patients with CP and hopes to promote its consideration in day-to-day practice.
BackgroundOur research has shown that patients with RA have higher proportions of peripheral blood CD3+CD8+CD28- Treg cells compared to healthy individuals. CD3+CD8+CD28- Treg cells in patients with RA have lost their ability to suppress lymphocyte proliferation1. Thus CD28 negativity may mark senescent T cells. CD572 CD45RA3,4 and killer-cell lectin like receptor G1 (KLRG1)5 cell surface molecules have been associated with CD8+ T cell activation and senescence. Defining the phenotypic signature of CD8+CD28- Treg cells will help establish their significance in the immunoregulation of RA.ObjectivesTo use immunofluorescence and flow cytometry to define the phenotype of CD3+CD8+CD28+/- cells in relation to early RA progression.MethodsThe effector characteristics of peripheral blood CD8 T cells were evaluated by flow cytometry. RA patients with established (n=21) and early disease (n=20) were recruited, and compared to twenty four healthy controls. The mean age of the subjects was 59 (SD=12.5), 25/38 (66%) were female, 27/38 (71%) were anti-CCP positive and 25/38 (66%) rheumatoid factor positive. The mean age for the controls was 43 (SD=11.6), 14/20 (70%) were female.ResultsConfirming our previous work, a significantly higher proportion of CD3+CD8+CD28- cells was observed in RA patients compared to healthy individuals (P=0.03) (Figure 1).Flow cytometric evaluation of peripheral blood demonstrated a significantly higher expression of CD57, CD45Ra and KLRG1 in CD28- compared to CD28+ T cells.Table 1.CD57, CD45Ra, KLRG1 and CD28 on CD3+CD8+ T cellsCD28−CD28+P value CD57+409<0.0001CD45Ra+38230.0026KLRG1+36200.0012A further evaluation of these markers revealed that 69% of the CD8+CD28- cell pool was KLRG1+, in comparison to 66% being CD57+ and 55% KLRG1+CD57+ double positive. This suggests that KLRG1 is a robust and clinically relevant marker of CD28- T cells in RA. Our current research is investigating the significance of KLRG1 and CD8+CD28- cells as prognostic markers in RA.ConclusionsCD3+CD8+CD28- cells are enriched in the peripheral blood of RA patients. KLRG1 expression is increased in line with CD57 and CD45Ra in CD8+CD28- cells, and will be used to evaluate the functional significance of these cells in relation to their activation status and potential senescence in the immunoregulation of RA pathogenesis.References Ceeraz S, Hall C, Choy EH, Spencer J, Corrigall VM. Defective CD8+CD28+ regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy. Clin Exp Immunol. 2013 Oct;174(1):18–26.Progressive decrease of CD8high+ CD28+ CD57- cells with ageing.Merino J, Martínez-González MA, Rubio M, Inogés S, Sánchez-Ibarrola A, Subirá ML Clin Exp Immunol. 1998 Apr; 112(1):48–51.CD28(-)CD8(+) T cells do not contain unique clonotypes and are therefore dispensable. Weinberger B, Welzl K, Herndler-Brandstetter D, Parson W, Grubeck-Loebenstein BImmunol Lett. 2009 Dec 2; 127(1):27–32.KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction ...
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