Myeloid-derived suppressor cells mediate tolerance induction in autoimmune disease

In multiple sclerosis (MS) T cells aberrantly recognize self‐peptides of the myelin sheath and attack the central nervous system (CNS). Antigen‐specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non‐specific immunosuppressive drugs, is a promising approach to combat autoimmune disease, but the cellular mechanisms behind successful therapy remain poorly understood. Myeloid‐derived suppressor cells (MDSCs) have been studied intensively in the field of cancer and to a lesser extent in autoimmunity. Because of their suppressive effect on the immune system in cancer, we hypothesized that the development of MDSCs and their interaction with CD4(+) T cells could be beneficial for antigen‐specific immunotherapy. Hence, changes in the quantity, phenotype and function of MDSCs during tolerance induction in our model of MS were evaluated. We reveal, for the first time, an involvement of a subset of MDSCs, known as polymorphonuclear (PMN)‐MDSCs, in the process of tolerance induction. PMN‐MDSCs were shown to adopt a more suppressive phenotype during peptide immunotherapy and inhibit CD4(+) T‐cell proliferation in a cell‐contact‐dependent manner, mediated by arginase‐1. Moreover, increased numbers of tolerogenic PMN‐MDSCs, such as observed over the course of peptide immunotherapy, were demonstrated to provide protection from disease in a model of experimental autoimmune encephalomyelitis

Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-β1

Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-β1.BackgroundVarious renal cell types have been shown to contribute to the excessive matrix deposition observed in diabetic nephropathy. The present study examined the effect of high ambient glucose and transforming growth factor-β1 (TGF-β1) on matrix production by human renal fibroblasts.MethodsHuman renal fibroblasts (TK173) were used to examine the effects of high glucose and TGF-β1 on fibronectin and collagen type III expression. Stable transfectants were generated of TK173 cells expressing a dominant negative TGF-β type II receptor. Matrix components were measured in enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR).ResultsFibronectin secretion by renal fibroblasts was increased upon exposure to high glucose, but with delayed kinetics compared to TGF-β1-induced fibronectin. Exposure to high glucose resulted in an increased secretion of latent TGF-β1. However, treatment with neutralizing pan-specific anti-TGF-β antibodies could not attenuate the effects of glucose. Furthermore, collagen type III was up-regulated by high glucose, but not by TGF-β1. Importantly, fibroblasts expressing a dominant negative TGF-β type II receptor were defective in TGF-β1-induced fibronectin production, whereas glucose-induced fibronectin and collagen type III were unaffected.ConclusionsThese data show that in renal fibroblasts exposure to high glucose can increase matrix production independent of endogenous TGF-β1. Although glucose activation is accompanied by an increased production of latent TGF-β1, which can have an important role in vivo, the data suggest involvement of alternative growth factors in the mechanism by which hyperglycemic conditions can modulate matrix accumulation in diabetic nephropathy

The Effect of Osteoarthritis of the Hip or Knee on Work Participation

In our systematic literature search, we included studies involving patients with hip or knee osteoarthritis (OA) and outcome measures of work participation. Methodological quality was assessed using 11 criteria; a qualitative data analysis was performed. Fifty-three full-text articles were selected out of 1861 abstracts; finally, data were extracted from 14 articles. Design, populations, definitions, and measurements in the studies showed large variations; work outcomes were often only secondary objectives. The outcomes were summarized as showing a mild negative effect of OA on work participation. Many patients had paid work and managed to stay at work despite limitations. However, research on the effect of OA on work participation is scarce and the methodological quality is often insufficient. The longitudinal course of work participation in individuals with OA has not been described completely. (First Release June 15 2011; J Rheumatol 2011;38:1835-43; doi:10.3899/jrheum.101210

Regenerative Medicine: Pharmacological Considerations and Clinical Role in Pain Management

Purpose of review: Low back pain affects at least 80% of individuals at some point in their lifetime and is the fifth most common reason for physician visits in the USA. Treatment of an acute episode of LBP generally includes rest, activity modification, physical therapy, NSAIDs, and patient education. Recent findings: A small percentage of patients will develop chronic pain lasting > 6 months duration. Platelet-rich plasma (PRP) is one of the main pillars of regenerative medicine, as its release of bioactive proteins supports the aim of RM of restoring the anatomical function in degenerative conditions. Mesenchymal stem cells (MSCs) are multipotent stem cells, multipotent progenitor cells, or marrow stromal cells found in various body tissues, including bone marrow, lung, and adipose tissue. Evidence from well-designed case-control or cohort studies for the use of PRP and MSCs in lumbar facet joint, lumbar epidural, and sacroiliac joint injections is currently described as level IV evidence. PRP and MSCs are used autogenously to help facilitate the healing process, and their injection has been studied in the long-term management of discogenic low back pain. PRP has been compared to steroid injections in the sacroiliac joint for chronic low back pain, with favorable results. MSCs have also been shown to be useful in intervertebral disc regeneration and treatment of chronic low back pain associated with degenerative disc disease. Currently, the price for these treatments is extremely high, and thus the standard of care continues to be steroid injections and other treatments. This could change, however, with more robust data and research on the safety and long-term efficacy of biologics compared to other interventional management

Cost-Effectiveness of Radiofrequency Denervation for Patients With Chronic Low Back Pain:The MINT Randomized Clinical Trials

OBJECTIVES: To evaluate the cost-effectiveness of radiofrequency denervation when added to a standardized exercise program for patients with chronic low back pain. METHODS: An economic evaluation was conducted alongside 3 pragmatic multicenter, nonblinded randomized clinical trials (RCTs) in The Netherlands with a follow up of 52 weeks. Eligible participants were included between January 1, 2013, and October 24, 2014, and had chronic low back pain; a positive diagnostic block at the facet joints (n = 251), sacroiliac (SI) joints (n = 228), or a combination of facet joints, SI joints, and intervertebral discs (n = 202); and were unresponsive to initial conservative care. Quality-adjusted life-years (QALYs) and societal costs were measured using self-reported questionnaires. Missing data were imputed using multiple imputation. Bootstrapping was used to estimate statistical uncertainty. RESULTS: After 52 weeks, no difference in costs between groups was found in the facet joint or combination RCT. The total costs were significantly higher for the intervention group in the SI joint RCT. The maximum probability of radiofrequency denervation being cost-effective when added to a standardized exercise program ranged from 0.10 in the facet joint RCT to 0.17 in the SI joint RCT irrespective of the ceiling ratio, and 0.65 at a ceiling ratio of €30 000 per QALY in the combination RCT. CONCLUSIONS: Although equivocal among patients with symptoms in a combination of the facet joints, SI joints, and intervertebral discs, evidence suggests that radiofrequency denervation combined with a standardized exercise program cannot be considered cost-effective from a societal perspective for patients with chronic low back pain originating from either facet or SI joints in a Dutch healthcare setting

Immune Responses in Healthy and Allergic Individuals Are Characterized by a Fine Balance between Allergen-specific T Regulatory 1 and T Helper 2 Cells

The mechanisms by which immune responses to nonpathogenic environmental antigens lead to either allergy or nonharmful immunity are unknown. Single allergen-specific T cells constitute a very small fraction of the whole CD4+ T cell repertoire and can be isolated from the peripheral blood of humans according to their cytokine profile. Freshly purified interferon-γ–, interleukin (IL)-4–, and IL-10–producing allergen-specific CD4+ T cells display characteristics of T helper cell (Th)1-, Th2-, and T regulatory (Tr)1–like cells, respectively. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals; in contrast, there is a high frequency of allergen-specific IL-4–secreting T cells in allergic individuals. Tr1 cells use multiple suppressive mechanisms, IL-10 and TGF-β as secreted cytokines, and cytotoxic T lymphocyte antigen 4 and programmed death 1 as surface molecules. Healthy and allergic individuals exhibit all three allergen-specific subsets in different proportions, indicating that a change in the dominant subset may lead to allergy development or recovery. Accordingly, blocking the suppressor activity of Tr1 cells or increasing Th2 cell frequency enhances allergen-specific Th2 cell activation ex vivo. These results indicate that the balance between allergen-specific Tr1 cells and Th2 cells may be decisive in the development of allergy

Depressive Symptoms and the Experience of Pleasure in Daily Life:An Exploration of Associations in Early and Late Adolescence

Although loss of pleasure (i.e., anhedonia) is one of the two core symptoms of depression, very little research has examined the relation between depressive symptoms and the experience of pleasure in daily life. This exploratory study in two population-based adolescent samples aimed to examine how depressive symptoms and anhedonia specifically were related to (1) the proportion and intensity of positive events, (2) mean and variability of positive affect (PA), (3) reactivity to positive events, and (4) reactivity to PA (i.e., whether PA elicits positive events). We used Experience Sampling to measure positive events and PA several times a day during 6 to 14 days in early (N = 284) and late (N = 74) adolescents. Results showed that depressive symptoms were related to a lower proportion and intensity of positive events, lower mean PA, and higher variability in PA regardless of sex and stage of adolescence. No clear evidence was found for differential reactivity to positive events or to PA. Anhedonia was not associated with most daily life experiences of pleasure. Our findings, though preliminary, suggest that although adolescents with many depressive symptoms experience less positive events and lower PA, they are able to enjoy pleasurable events to the same extent as individuals with fewer depressive symptoms

Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree

Background: Thoracic aortic aneurysm (TAA) is a potentially life-threatening disorder with a strong genetic component. The number of genes implicated in TAA has increased exponentially over the last decade. Approximately 20% of patients with TAA have a positive family history. As most TAA remain asymptomatic for a long time, screening of at risk relatives is warranted to prevent complications. Existing international guidelines lack detailed instructions regarding genetic evaluation and family screening of TAA patients. We aimed to develop a consensus document to provide medical guidance for all health care professionals involved in the recognition, diagnosis and treatment of patients with thoracic aortic disease and their relatives. Methods: A multidisciplinary panel of experts including cardiologists, cardiothoracic surgeons, clinical geneticists and general practitioners, convened to review and discuss the current literature, guidelines and clinical practice on genetic testing and family screening in TAA. Results: There is a lack of high-quality evidence in the literature. This consensus statement, based on the available literature and expert opinions, summarizes our recommendations in order to standardize and optimize the cardiogenetic care for patients and families with thoracic aortic disease. In particular, we provide criteria to identify those patients most likely to have a genetic predisposition, and discuss the preferred modality and frequency of screening in their relatives. Conclusions: Age, family history, aortic size and syndromic features determine who is advised to have genetic testing as well as screening of first-degree relatives. There is a need for more prospective multicenter studies to optimize current recommendations