Thomas Hügle

T cells in systemic sclerosis: a reappraisal

SSc is an autoimmune disease characterized by inflammation and extracellular matrix deposition that ultimately leads to loss of organ function. T cells appear to play a prominent role in its pathogenesis. The evidence for this comes from their being at the site of fibrosis, their activated phenotype and alteration in their number and frequency in peripheral blood. This review examines the role of T cells in the pathogenesis of SSc and specifically examines the key soluble profibrotic mediators (IL-4, IL-6, IL-13) secreted by Th2 cells and their interactions with fibroblasts that deposit excess extracellular matrix leading to fibrosis. We finally examine possible therapeutic options in targeting T-cell mediators to disrupt the cellular interactions between T cells and fibroblasts that serve to drive the fibrotic response. One of the factors driving fibrosis is IL-6 and this can be neutralized in vivo not only to limit IL-6-driven tissue fibrosis but concomitantly to suppress switching of Tregs to Th17 T cells that will provide more IL-6, thus perpetuating the fibrosis. Taken together, these data implicate the role of T cells in SSc and suggest that Th2-polarized T cells and the fibrotic mediators subsequently released directly induce fibrosis. Targeting such cytokines may be therapeutic not only in SSc but more generally in diseases where fibrosis is directed by inflammatory signals.

Biomechanics and pathomechanisms of osteoarthritis.

Today, the most frequent chronic musculoskeletal disorder and the leading cause of disability in the elderly is osteoarthritis (OA). Approximately 43 million people in the United States and 15% of the world population are affected. Due to demographic changes, the incidence of OA is rapidly increasing, leading to an ascending socioeconomical and personal burden. Despite the exact cause of OA remains unknown, the pathogenic role of biomechanical dysfunction in OA is well established. For weight-bearing joints altered loading mechanisms, increased mechanical forces and changed biomechanics are significant contributing factors for initiation and progression of OA. Thus, OA is a disease of the whole joint, including muscles, tendons, ligaments, synovium and bone. This review focuses on the influence of biomechanics on the pathogenesis and progression of OA. We notably illustrate the pathological bioreactivity of soft tissues, subchondral bone and joint inflammation. Procedures, conservative or surgical, which actively alter the biomechanics of the lower limb, are promising strategies to treat symptoms as well as to influence disease progression in OA.

Allogeneic hematopoietic SCT for patients with autoimmune diseases

Allogeneic hematopoietic SCT (HSCT) has been used as treatment for single patients with autoimmune diseases (AD). To summarise currently available information, we analyzed all patients who underwent allogeneic HSCT for AD and who reported to the European Group for Blood and Marrow Transplantation (EBMT) database. Thirty-five patients receiving 38 allogeneic transplantations for various hematological and non-hematological AD were identified. Four patients had had an allogeneic HSCT for a conventional hematological indication in the past. Fifty-five per cent of the transplantation procedures led to a complete clinical response of the refractory AD and 23% to at least a partial response. The median duration of response at the last follow-up was 70.7 (15.2–130) months. Three patients relapsed at a median of 12.3 months after HSCT. Treatment-related mortality at 2 years was 22.1% (95% CI: 7.3–36.9%). Two deaths were caused by progression of AD. The probability of survival at 2 years was 70%. No single factor predicting the outcome could be identified. The retrospective nature of this study and the heterogeneous, partly incomplete data are its limitations. However, allogeneic HSCT can induce remission in patients suffering from refractory AD. These data provide the basis for carefully conducted prospective trials.

Interleukin-6, its role in fibrosing conditions.

Interleukin-6 is a classic pro-inflammatory cytokine needed to mount an effective immune response. It is secreted by a wide array of cell types, however, its target cells are more restricted, due to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor. This therefore limits the amount of cells that can respond to IL-6. Transsignalling, the shedding of the membrane bound form of the IL-6 receptor (sIL-6R) into the local microenvironment, greatly increases the range of cells that can respond e.g. as part of a wound healing response necessary to restore the homeostatic balance. Therefore, tight regulation of IL-6 signalling must occur to stop an inappropriate wound healing response occurring. This review focusses on the role of IL-6 in inflammation and fibrosing conditions, with a particular emphasis on systemic sclerosis (SSc), a chronic autoimmune disease in which a classical hallmark of fibrosis occurs. This fibrosis, in particular the skin and internal organs, leads to contractures and internal organ failure respectively with potential fatal consequences. In this review we will discuss the biology of IL-6 in the context of fibrosing conditions such as SSc and argue why molecular targeting of IL-6 is a promising therapeutic target.

The value of serum procalcitonin level for differentiation of infectious from noninfectious causes of fever after orthopaedic surgery

BACKGROUND Early diagnosis of postoperative orthopaedic infections is important in order to rapidly initiate adequate antimicrobial therapy. There are currently no reliable diagnostic markers to differentiate infectious from noninfectious causes of postoperative fever. We investigated the value of the serum procalcitonin level in febrile patients after orthopaedic surgery. METHODS We prospectively evaluated 103 consecutive patients with new onset of fever within ten days after orthopaedic surgery. Fever episodes were classified by two independent investigators who were blinded to procalcitonin results as infectious or noninfectious origin. White blood-cell count, C-reactive protein level, and procalcitonin level were assessed on days 0, 1, and 3 of the postoperative fever. RESULTS Infection was diagnosed in forty-five (44%) of 103 patients and involved the respiratory tract (eighteen patients), urinary tract (eighteen), joints (four), surgical site (two), bloodstream (two), and soft tissues (one). Unlike C-reactive protein levels and white blood-cell counts, procalcitonin values were significantly higher in patients with infection compared with patients without infection on the day of fever onset (p = 0.04), day 1 (p = 0.07), and day 3 (p = 0.003). Receiver-operating characteristics demonstrated that procalcitonin had the highest diagnostic accuracy, with a value of 0.62, 0.62, and 0.71 on days 0, 1, and 3, respectively. In a multivariate logistic regression analysis, procalcitonin was a significant predictor for postoperative infection on days 0, 1, and 3 of fever with an odds ratio of 2.3 (95% confidence interval, 1.1 to 4.4), 2.3 (95% confidence interval, 1.1 to 5.2), and 3.3 (95% confidence interval, 1.2 to 9.0), respectively. CONCLUSIONS Serum procalcitonin is a helpful diagnostic marker supporting clinical and microbiological findings for more reliable differentiation of infectious from noninfectious causes of fever after orthopaedic surgery.

Tumor necrosis factor–costimulated T lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts

OBJECTIVE The role of tumor necrosis factor (TNF) in systemic sclerosis (SSc) remains controversial. The present study was undertaken to investigate the influence of TNF receptor (TNFR)-costimulated lymphocytes on collagen expression in fibroblasts. METHODS TNFR expression on mononuclear cells from the dermis and blood of SSc patients was assessed by flow cytometry. Peripheral blood CD3+ lymphocytes were activated with CD3/CD28 beads and costimulated with TNFR-selective variants. Expression of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), IL-10, and IL-13 was detected by enzyme-linked immunosorbent assay or quantitative reverse transcription-polymerase chain reaction. Healthy fibroblasts were incubated with conditioned media from TNFR-costimulated T lymphocytes, and type I collagen expression was quantified. RESULTS TNFRI and TNFRII were up-regulated on dermal T lymphocytes from patients with diffuse cutaneous SSc. TNFRII expression correlated with skin thickening. After CD3/CD28 activation, peripheral blood lymphocytes from SSc patients produced more IL-6, sIL-6R, and IL-13 compared to healthy lymphocytes. Costimulation with TNFRI-selective ligands and soluble TNF further increased IL-6 expression, whereas costimulation with TNFRII led to greater release of sIL-6R. IL-10 expression, which normally occurs after TNFRII costimulation, was impaired in SSc T cells. Supernatants of TNF-costimulated SSc lymphocytes induced higher type I collagen expression in fibroblasts, which was partially reversible by dual inhibition of IL-6 and IL-13. Expression of TNFR and IL-6 in the dermis was reversible in a patient who received lymphoablative therapy prior to autologous hematopoietic stem cell transplantation. CONCLUSION TNF-costimulated T lymphocytes from SSc patients have a propensity to secrete profibrotic cytokines, while the ability to produce IL-10 is weakened. These results suggest that T lymphocytes in SSc support fibrosis, but might lack the capacity to resolve inflammation.

Mast cells are a source of transforming growth factor β in systemic sclerosis.

OBJECTIVE To describe the cellular source of transforming growth factor β (TGFβ) in the dermis of patients with systemic sclerosis (SSc). METHODS We performed electron microscopy (EM) with immunogold labeling on skin biopsy specimens from 7 patients with SSc and 3 healthy control subjects. For TGFβ quantification, the numbers of gold particles per square micron were calculated. The origin of mast cells was confirmed and quantified by toluidine blue staining and light microscopy. Degranulation was assessed on toluidine blue-stained sections and on EM images. RESULTS In all patients, active TGFβ was observed uniquely in mast cell vesicles, some of which were released into the extracellular space. Patients with progressive SSc and a more recent onset of non-Raynauds phenomenon symptoms had higher numbers of mast cells and gold particles per mast cell. Mast cells from healthy control subjects also contained active TGFβ but, in contrast to SSc samples, showed a resting character with no or low-level degranulation and uniformly dense osmiophilic vesicles. CONCLUSION Degranulation of skin mast cells can be an important mechanism of TGFβ secretion in SSc.

Aging and Osteoarthritis: An Inevitable Encounter?

Osteoarthritis (OA) is a major health burden of our time. Age is the most prominent risk factor for the development and progression of OA. The mechanistic influence of aging on OA has different facets. On a molecular level, matrix proteins such as collagen or proteoglycans are modified, which alters cartilage function. Collagen cross-linking within the bone results in impaired plasticity and increased stiffness. Synovial or fat tissue, menisci but also ligaments and muscles play an important role in the pathogenesis of OA. In the elderly, sarcopenia or other causes of muscle atrophy are frequently encountered, leading to a decreased stability of the joint. Inflammation in form of cellular infiltration of synovial tissue or subchondral bone and expression of inflammatory cytokines is more and more recognized as trigger of OA. It has been demonstrated that joint movement can exhibit anti-inflammatory mechanisms. Therefore physical activity or physiotherapy in the elderly should be encouraged, also in order to increase the muscle mass. A reduced stem cell capacity in the elderly is likely associated with a decrease of repair mechanisms of the musculoskeletal system. New treatment strategies, for example with mesenchymal stem cells (MSC) are investigated, despite clear evidence for their efficacy is lacking.

Educational quality of YouTube videos on knee arthrocentesis.

BackgroundKnee arthrocentesis is a commonly performed diagnostic and therapeutic procedure in rheumatology and orthopedic surgery. Classic teaching of arthrocentesis skills relies on hands-on practice under supervision. Video-based online teaching is an increasingly utilized educational tool in higher and clinical education. YouTube is a popular video-sharing Web site that can be accessed as a teaching source. ObjectiveThe objective of this study was to assess the educational value of YouTube videos on knee arthrocentesis posted by health professionals and institutions during the period from 2008 to 2012. MethodsThe YouTube video database was systematically searched using 5 search terms related to knee arthrocentesis. Two independent clinical reviewers assessed videos for procedural technique and educational value using a 5-point global score, ranging from 1 = poor quality to 5 = excellent educational quality. As validated international guidelines are lacking, we used the guidelines of the Swiss Society of Rheumatology as criterion standard for the procedure. ResultsOf more than thousand findings, 13 videos met the inclusion criteria. Of those, 2 contained additional animated video material: one was purely animated, and one was a check list. The average length was 3.31 ± 2.28 minutes. The most popular video had 1388 hits per month. Our mean global score for educational value was 3.1 ± 1.0. Eight videos (62 %) were considered useful for teaching purposes. Use of a “no-touch” procedure, meaning that once disinfected the skin remains untouched before needle penetration, was present in all videos. Six videos (46%) demonstrated full sterile conditions. There was no clear preference of a medial (n = 8) versus lateral (n = 5) approach. ConclusionsA discreet number of YouTube videos on knee arthrocentesis appeared to be suitable for application in a Web-based format for medical students, fellows, and residents. The low-average mean global score for overall educational value suggests an improvement of future video-based instructional materials on YouTube would be necessary before regular use for teaching could be recommended.

Toll-like receptor-mediated, enhanced production of profibrotic TIMP-1 in monocytes from patients with systemic sclerosis: role of serum factors

Objectives To investigate whether monocytes contribute to matrix deposition in systemic sclerosis (SSc) by production of tissue-inhibitor of metalloproteinase-1 (TIMP-1). Methods Matrix metalloproteinase-1 (MMP-1) and TIMP-1 expression and secretion were measured by qRT-PCR and ELISA in circulating monocytes from patients with SSc, patients with rheumatoid arthritis (RA) and healthy controls (HC) and in healthy monocytes cultured in the presence of SSc or HC serum samples. Production of TIMP-1 was determined in response to a panel of Toll-like receptor (TLR) agonists and MyD88 inhibitory peptide. The functional effect of conditioned media from SSc and HC serum samples or TLR8-stimulated monocytes was studied in an MMP-1 activity assay. Results TIMP-1 production by monocytes was upregulated in patients with SSc compared with patients with RA and HC. Incubation of HC monocytes with SSc serum samples resulted in functionally active TIMP-1 production. However, pretreatment with MyD88 inhibitor, but not control peptide, decreased TIMP-1 secretion. TIMP-1 production was significantly stronger when SSc and HC monocytes were stimulated with TLR8 (ssRNA) agonist, but the response was more pronounced in SSc monocytes. TIMP-1 production after TLR stimulation was also strongly reduced in the presence of MyD88 inhibitory peptide or in the monocytes isolated from a patient with a genetic TLR signalling defect. MMP-1 activity was significantly inhibited in media from serum samples or TLR8-stimulated monocytes indicative of functional TIMP activity. Conclusions This study demonstrates profibrotic properties of circulating monocytes from patients with SSc and a key role for TLR signalling, particularly TLR8, in TIMP-1 secretion and matrix remodelling.