A personalised delisting strategy enables successful kidney transplantation in highly sensitised patients with preformed donor-specific anti HLA antibodies.

This study investigates kidney transplant outcomes in highly sensitised patients after implementing a delisting strategy aimed at enabling transplantation despite preformed donor-specific antibodies (preDSA), with the goal of reducing acute antibody-mediated rejection (aAMR) risk. Fifty-three sensitised recipients underwent kidney transplant after delisting prohibited HLA antigens, focusing initially in low MFI antibodies (<5000), except for anti-HLA-DQ. If insufficient, higher MFI antibodies were permitted, especially for those without an immunogenic eplet pattern assigned.

Evidence of telomere attrition and a potential role for DNA damage in systemic sclerosis.

Background: To investigate the role of cell senescence in systemic sclerosis (SSc), we analyzed telomere shortening (TS) in SSc patients and the effect of targeting DNA damage in the bleomycin model of skin fibrosis.

Results: Telomere length (TL) in blood leukocytes of 174 SSc patients and 68 healthy controls was measured by Southern blot, and we found shorter age-standardized TL in SSc patients compared to healthy controls. TL was shorter in SSc patients with ILD compared to those without ILD and in anti-topoisomerase I positive compared to anti-centromere positive patients.

TFAM-deficient mouse skin fibroblasts - an ex vivo model of mitochondrial dysfunction.

Mitochondrial dysfunction associates with several pathological processes and contributes to chronic inflammatory and ageing-related diseases. Mitochondrial transcription factor A (TFAM) plays a critical role in maintaining mtDNA integrity and function. Taking advantage of Tfamfl/fl UBC-Cre/ERT2+/+ mice to investigate mitochondrial dysfunction in the stromal cell component, we describe an inducible in vitro model of mitochondrial dysfunction by stable depletion of TFAM in primary mouse skin fibroblasts (SK-FBs) after 4-hydroxytamoxifen (4-OHT) administration.

IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms.

Introduction: The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF.

Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype.

Background: Accumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF).

Results: The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors.

Hif-1α Knockdown Reduces Glycolytic Metabolism and Induces Cell Death of Human Synovial Fibroblasts Under Normoxic Conditions.

Increased glycolysis and HIF-1α activity are characteristics of cells under hypoxic or inflammatory conditions. Besides, in normal O environments, elevated rates of glycolysis support critical cellular mechanisms such as cell survival. The purpose of this study was to analyze the contribution of HIF-1α to the energy metabolism and survival of human synovial fibroblasts (SF) under normoxic conditions.

CD271(+) stromal cells expand in arthritic synovium and exhibit a proinflammatory phenotype.

Background: CD271(+) stromal cells (SCs) with multipotent stem cell capacity have been identified in synovial tissues, but their functional significance is unknown. We analyzed the distribution of CD271(+) cells in inflammatory synovial tissues as well as their ex vivo immunomodulatory and inflammatory phenotypes.

Methods: CD271 expression was analyzed by immunohistochemistry in synovial tissues and by flow cytometry in primary adherent synovial cell cultures from rheumatoid arthritis (RA), osteoarthritis (OA), and non-inflammatory control tissues.

Clinicopathological correlations of podoplanin (gp38) expression in rheumatoid synovium and its potential contribution to fibroblast platelet crosstalk.

Introduction: Synovial fibroblasts (SF) undergo phenotypic changes in rheumatoid arthritis (RA) that contribute to inflammatory joint destruction. This study was undertaken to evaluate the clinical and functional significance of ectopic podoplanin (gp38) expression by RA SF.

Methods: Expression of gp38 and its CLEC2 receptor was analyzed by immunohistochemistry in synovial arthroscopic biopsies from RA patients and normal and osteoarthritic controls.

Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma.

Vitamin D analogues can reduce TGF-β pro-fibrotic signaling in dermal fibroblasts, but they may also induce a potentially pro-fibrotic thymic stromal lymphopoietin (TSLP)-dependent Th2 cytokine local response. We have analyzed the net effect of topical vitamin D analogue calcipotriol (CPT) on the cytokine profile and the development of fibrosis in experimental model of bleomycin-induced fibrosis. Mice were simultaneously treated with topical CPT or vehicle cream and skin fibrosis was measured by collagen deposition, Masson's trichrome staining and hydroxyproline content.

A profibrotic role for thymic stromal lymphopoietin in systemic sclerosis.

Objective: [corrected] Systemic sclerosis (SSc) is an autoimmune disease characterised by progressive fibrosis. Although SSc shares pathogenetic features with other autoimmune diseases, the participation of profibrotic Th2 cytokines is unique to SSc, but the mechanisms of Th2 skewing are unknown. We have analysed the expression and function of thymic stromal lymphopoietin (TSLP), a central regulator of Th2-mediated allergic inflammation, in human SSc, primary lung fibrosis and in a mouse model of scleroderma.

Transcriptome analysis reveals specific changes in osteoarthritis synovial fibroblasts.

Objective: Changes in rheumatoid arthritis synovial fibroblast (RASF) gene expression are usually defined by a comparison to osteoarthritis synovial fibroblasts (OASFs). This study was undertaken to analyse the transcriptome of OASFs as compared to RASFs and healthy synovial fibroblasts (HSFs).

Methods: The authors used microarray messenger RNA expression profiling of synovial fibroblasts cultured from osteoarthritis (OA), rheumatoid arthritis and normal synovial tissues.

CXCL12γ isoform is expressed on endothelial and dendritic cells in rheumatoid arthritis synovium and regulates T cell activation.

Objective: CXCL12γ is an alternative splicing isoform of CXCL12 with enhanced affinity for heparan sulfate (HS) proteoglycans. This study was undertaken to investigate the distribution and potential function of CXCL12γ in rheumatoid arthritis (RA) synovium and normal lymphoid tissue, where its immobilization to HS may be relevant in pathologic or homeostatic immune cell migration and activation.

Methods: Expression of CXCL12 or CXCL12γ was immunodetected in RA and normal synovium, lymphoid tissue, and cultured cells with anti-pan-CXCL12 or anti-CXCL12γ-specific monoclonal antibodies.

Fibroblast abnormalities in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a chronic systemic disease characterized by autoimmunity, vascular lesions and progressive fibrosis. The fibrotic component is dominant in SSc compared with other vascular or autoimmune diseases and determines its prognosis and therapeutic refractoriness. Fibroblasts are responsible for abnormal extracellular matrix accumulation.

Synovial fibroblast hyperplasia in rheumatoid arthritis: clinicopathologic correlations and partial reversal by anti-tumor necrosis factor therapy.

Objective: Synovial fibroblast (SF) hyperplasia contributes to the pathogenesis of rheumatoid arthritis (RA), but quantitative information on this process is scarce. This study was undertaken to evaluate the fibroblast-specific marker Hsp47 as a quantitative marker for SFs and to analyze its clinicopathologic correlates and evolution after anti-tumor necrosis factor α (anti-TNFα) therapy.

Methods: Synovial biopsy samples were obtained from 48 patients with RA and 20 controls who were healthy or had osteoarthritis (OA).

The transcriptional response of normal and rheumatoid arthritis synovial fibroblasts to hypoxia.

Objective: Hypoxia is a prominent feature in rheumatoid arthritis (RA) synovium. However, its contribution to the pathogenesis of RA remains unclear. We undertook this study to systematically characterize the changes in gene expression induced by hypoxia in synovial fibroblasts.

CXCL12 gene expression is upregulated by hypoxia and growth arrest but not by inflammatory cytokines in rheumatoid synovial fibroblasts.

Objectives: CXCL12 is a constitutively expressed chemokine with important homeostatic functions. Increased CXCL12 expression has been observed in several inflammatory conditions, including rheumatoid arthritis (RA). This study was undertaken to identify potential mechanisms of regulation of CXCL12 gene expression by human fibroblasts under normal or inflammatory conditions.

Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy.

Background: Angiogenesis is considered an important factor in the pathogenesis of Rheumatoid Arthritis (RA) where it has been proposed as a therapeutic target. In other settings, active angiogenesis is characterized by pathologic, immature vessels that lack periendothelial cells. We searched for the presence of immature vessels in RA synovium and analyzed the dynamics of synovial vasculature along the course of the disease, particularly after therapeutic response to TNF antagonists.

Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia-inducible transcription factor 1alpha/vascular endothelial growth factor-mediated pathway in immunodeficient mice.

Objective: Hyperplasia and phenotypic changes in fibroblasts are often observed in chronic inflammatory lesions, and yet the autonomous pathogenic contribution of these changes is uncertain. The purpose of this study was to analyze the intrinsic ability of fibroblasts from chronically inflamed synovial tissue to drive cell recruitment and angiogenesis.

Methods: Fibroblasts from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as fibroblasts from healthy synovial tissue and healthy skin, were cultured and subcutaneously engrafted into immunodeficient mice.

Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder characterized by chronic lymphoproliferation, autoimmune manifestations and expansion of TCRalphabeta+CD4-CD8- lymphocytes. The main pathogenic factor is a defective Fas-mediated apoptosis generally caused by mutations in the Fas gene. This report describes a new heterozygous Fas gene mutation in a boy with clinical and immunological features of ALPS.

A modified cord blood collection method achieves sufficient cell levels for transplantation in most adult patients.

Umbilical cord blood transplantation (UCBT) has been used increasingly in both pediatric and adult patients. The total nucleated cell (NC) dose infused is the most critical factor in determining speed of engraftment and survival. Using standard collection techniques, the mean NC content of UCB units is about 10 x 10(8) and only 25% of these units reach the target cell dose of 2 x 10(7)/kg in UCBT patients weighing 50-70 kg.

HLA haplotypes associated with hemochromatosis mutations in the Spanish population.

Background: The present study is an analysis of the frequencies of HLA-A and -B antigens and HLA haplotypes in two groups of individuals homozygous for the two main HFE mutations (C282Y and H63D) and a group heterozygous for the S65C mutation.

Methods: The study population includes: 1123 healthy individuals, 100 homozygous for the C282Y mutation, 138 homozygous for the H63D mutation and 17 heterozygous for the S65C mutation. HFE and HLA alleles were detected using DNA-based and microlymphocytotoxicity techniques respectively.