The neuropeptide neuromedin U promotes autoantibody-mediated arthritis

Introduction: Neuromedin U (NMU) is a neuropeptide with pro-inflammatory activity. The primary goal of this study was to determine if NMU promotes autoantibody-induced arthritis. Additional studies addressed the cellular source of NMU and sought to define the NMU receptor responsible for its pro-inflammatory effects. Methods: Serum containing arthritogenic autoantibodies from K/BxN mice was used to induce arthritis in mice genetically lacking NMU. Parallel experiments examined whether NMU deficiency impacted the early mast-cell-dependent vascular leak response induced by these autoantibodies. Bone-marrow chimeric mice were generated to determine whether pro-inflammatory NMU is derived from hematopoietic cells or stromal cells. Mice lacking the known NMU receptors singly and in combination were used to determine susceptibility to serum-transferred arthritis and in vitro cellular responses to NMU. Results: NMU-deficient mice developed less severe arthritis than control mice. Vascular leak was not affected by NMU deficiency. NMU expression by bone-marrow-derived cells mediated the pro-arthritogenic effect. Deficiency of all of the known NMU receptors, however, had no impact on arthritis severity and did not affect the ability of NMU to stimulate intracellular calcium flux. Conclusions: NMU-deficient mice are protected from developing autoantibody-induced inflammatory arthritis. NMU derived from hematopoietic cells, not neurons, promotes the development of autoantibody-induced inflammatory arthritis. This effect is mediated by a receptor other than the currently known NMU receptors

Abrogation of antibody-induced arthritis in mice by a self-activating viridin prodrug and association with impaired neutrophil and endothelial cell function

Objective: To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. Methods: The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin–selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil–endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. Results: SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor α was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. Conclusion: A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions.National Institutes of Health (U.S.) (Grant P01-AI-054904)National Institutes of Health (U.S.) (Grant R01-EB-001872)National Institutes of Health (U.S.) (Grant R01-AR-046580)National Institutes of Health (U.S.) (Grant R24-CA-92782)National Institutes of Health (U.S.) (Grant P50-CA-86355

Calcifications due to Mitral Valve Disease Induced by Rheumatoid Arthritis in K/B.g7 Mice

Background and Hypothesis: Rheumatoid arthritis (RA) is a rheumatic autoimmune disease wherein the host generates self-antibodies that target the synovial lining of joints. However, it’s been observed that patients with RA also develop Mitral Valve Disease (MVD), although the mechanism is not very well known. In my project, I focused on the physiological changes of the heart during the formation of MVD, specifically focusing on calcifications and whether they form on the inflamed valve. I hypothesized that calcifications are developing during disease progression, resulting in advancement of the inflammation cycle. Experimental Design or Project Methods: A total of thirteen mouse hearts were removed and stored in OTC at -80 C: 5 K/B.g7 (7 months), 5 K/B.g7 (8 weeks) and 3 B6 (1.5 years). The hearts were sectioned and stained using calcium-staining Alizarin Red S. Additional sections were also stained with Hemotoxylin and Eosin stain. Results: From my analysis, it was apparent that there were no calcifications on the mitral valves in any of the samples. Pigmentation was apparent, but potential calcium was ruled out when compared to the H&E stains. There were heavy calcium deposits in the aorta and aortic valve in forty percent of the MVD samples. Additionally, calcium was seen near the apex of the left ventricle in three of the ten MVD samples. Conclusion and Potential Impact: In conclusion, it doesn’t appear that calcification occurs in the mitral valve, neither in the early nor late onset of RA. However, I pursued the calcifications seen in the aorta because of previous research done with calcifications seen in RA mice eating a high-fat diet. Currently, I am investigating further with the entirety of the aorta and staining to see if the calcification is isolated near the valve or if the calcifications spread. I am hoping that my findings will assist in identifying the physiological changes that are seen in rheumatoid arthritis

Autoantibodies in the Pathogenesis, Diagnosis, and Prognosis of Juvenile Idiopathic Arthritis

Autoantibody production occurs in juvenile idiopathic arthritis (JIA) and numerous other autoimmune diseases. In some conditions, the autoantibodies are clearly pathogenic, whereas in others the roles are less defined. Here we review various autoantibodies associated with JIA, with a particular focus on antinuclear antibodies and antibodies recognizing citrullinated self-antigens. We explore potential mechanisms that lead to the development of autoantibodies and the use of autoantibody testing in diagnosis and prognosis. Finally, we compare and contrast JIA-associated autoantibodies with those found in adults with rheumatoid arthritis (RA)

Neutrophils in animal models of autoimmune disease

Neutrophils have traditionally been thought to play only a peripheral role in the genesis of many autoimmune and inflammatory diseases. However, recent studies in a variety of animal models suggest that these cells are central to the initiation and propagation of autoimmunity. The use of mouse models, which allow either deletion of neutrophils or the targeting of specific neutrophil functions, has revealed the many complex ways these cells contribute to autoimmune/inflammatory processes. This includes generation of self antigens through the process of NETosis, regulation of T-cell and dendritic cell activation, production of cytokines such as BAFF that stimulate self-reactive B-cells, as well as indirect effects on epithelial cell stability. In comparing the many different autoimmune models in which neutrophils have been examined, a number of common underlying themes emerge - such as a role for neutrophils in stimulating vascular permeability in arthritis, encephalitis and colitis. The use of animal models has also stimulated the development of new therapeutics that target neutrophil functions, such as NETosis, that may prove beneficial in human disease. This review will summarize neutrophil contributions in a number of murine autoimmune/inflammatory disease models. © 2016 Elsevier Ltd

Inflammatory arthritis can be reined in by CpG-induced DC–NK cell cross talk

Unmethylated CpG-oligodeoxynucleotides (ODNs) are generally thought of as potent adjuvants with considerable therapeutic potential to enhance immune responses against microbes and tumors. Surprisingly, certain so-called stimulatory CpG-ODNs strongly inhibited the effector phase of inflammatory arthritis in the K/BxN serum transfer system, either preventively or therapeutically. Also unexpected was that the inhibitory influence did not depend on the adaptive immune system cells mobilized in an immunostimulatory context. Instead, they relied on cells of the innate immune system, specifically on cross talk between CD8α+ dendritic cells and natural killer cells, resulting in suppression of neutrophil recruitment to the joint, orchestrated through interleukin-12 and interferon-γ. These findings highlight potential applications of CpG-ODNs and downstream molecules as antiinflammatory agents

Alternative Markers of Performance in Simulation: Where We Are and Where We Need To Go

This article on alternative markers of performance in simulation is the product of a session held during the 2017 Academic Emergency Medicine Consensus Conference â Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes.â There is a dearth of research on the use of performance markers other than checklists, holistic ratings, and behaviorally anchored rating scales in the simulation environment. Through literature review, group discussion, and consultation with experts prior to the conference, the working group defined five topics for discussion: 1) establishing a working definition for alternative markers of performance, 2) defining goals for using alternative performance markers, 3) implications for measurement when using alternative markers, identifying practical concerns related to the use of alternative performance markers, and 5) identifying potential for alternative markers of performance to validate simulation scenarios. Five research propositions also emerged and are summarized.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142535/1/acem13321_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142535/2/acem13321.pd

Barriers and alternatives to pediatric rheumatology referrals: survey of general pediatricians in the United States

BACKGROUND: Access to pediatric rheumatology (PR) care is limited, however the impact that limited access to PR has on pediatricians has not been examined. The goal of this study was to investigate barriers to PR referrals and resulting alternative referral patterns among primary pediatricians. METHODS: A web-based survey was emailed to primary pediatricians practicing in Minnesota, North Dakota, and South Dakota in order to investigate access to PR care issues. Basic descriptive analysis was performed. RESULTS: The response rate was 15 % (93/609). Twenty-nine percent (27/92) of respondents’ clinics were at least two hours by car from a pediatric rheumatologist, and 9 % (8/92) were more than six hours away. Ninety-two percent (85/92) had referred a patient to PR at least once, but 89 % (83/93) had experienced a situation in which they considered a referral to PR but ultimately did not. Many had referred to other subspecialists instead: 29 % (24/83) to pediatric infectious disease, 20 % to adult rheumatology, and 12 % to pediatric orthopedics, while 34 % managed the patient themselves. Thirty-five percent (32/60) had referred to an adult rheumatologist, commonly due to decreased travel (44 %), while physician preference was never selected as a reason. CONCLUSION: Pediatricians often refer children with possible rheumatic disease to specialists other than PR mainly due to long travel distances. Referral to adult rheumatologists occurs, but not based on pediatrician preference. These findings suggest that the PR workforce is inadequate to meet demand, at least in the Upper Midwest. Interventions are needed to improve access to PR care