Rheumatoid arthritis (RA)-associated IgG antibodies such as anti-citrullinated protein antibodies (ACPAs) have diverse glycosylation variants; however, key sugar chains modulating the arthritogenic activity of IgG remain to be clarified. Here, we show that reduced sialylation is a common feature of RA-associated IgG in humans and in mouse models of arthritis. Genetically blocking sialylation in activated B cells results in exacerbation of joint inflammation in a collagen-induced arthritis (CIA) model. On the other hand, artificial sialylation of anti-type II collagen antibodies, including ACPAs, not only attenuates arthritogenic activity, but also suppresses the development of CIA in the antibody-infused mice, whereas sialylation of other IgG does not prevent CIA. Thus, our data demonstrate that sialylation levels control the arthritogenicity of RA-associated IgG, presenting a potential target for antigen-specific immunotherapy.

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Objective. The hyaluronan receptor CD44 provides chondrocytes with a mechanism for sensing and responding to changes in the extracellular matrix. The purpose of this study was to document the fragmentation and loss of CD44 and to determine the likely mechanisms involved.Methods. A polyclonal anti-CD44 cytotail antibody was generated to detect CD44 fragmentation by Western blot analysis. Chondrocytes were isolated from human or bovine articular cartilage. Primary articular chondrocytes were treated with interleukin-1␤ (IL-1␤), hyaluronan oligosaccharides, or phorbol myristate acetate or were passaged and subcultured in monolayer to induce dedifferentiation. Conditions that altered the capacity of CD44 to transit into lipid rafts, or pharmacologic inhibitors of metalloproteinase or ␥-secretase activity were used to define the mechanism of fragmentation of CD44.Results. Chondrocytes from osteoarthritic cartilage exhibited CD44 fragmentation as low molecular mass bands, corresponding to the CD44-EXT and CD44-ICD bands. Following dedifferentiation of chondrocytes or treatment of primary chondrocytes with hyaluronan oligosaccharides, IL-1␤, or phorbol myristate acetate, CD44 fragmentation was enhanced. Subsequent culture of the dedifferentiated chondrocytes in 3-dimensional alginate beads rescued the chondrocyte phenotype and diminished the fragmentation of CD44.Fragmentation of CD44 in chondrocytes was blocked in the presence of the metalloproteinase inhibitor GM6001 and the ␥-secretase inhibitor DAPT.Conclusion. CD44 fragmentation, consistent with a signature pattern reported for sequential metalloproteinase/␥-secretase cleavage of CD44, is a common metabolic feature of chondrocytes that have undergone dedifferentiation in vitro and osteoarthritic chondrocytes. Transit of CD44 into lipid rafts may be required for its fragmentation.In cartilage, cell-matrix interactions are the primary means by which chondrocytes sense changes in the extracellular environment and signal a reparative response. Hyaluronan (HA) binding to the CD44 receptor is a key player in such interactions. In articular cartilage, HA serves as the core filament of the proteoglycan aggregate, composed of HA, link protein, and the major cartilage proteoglycan aggrecan, establishing essential biomechanical properties of the cartilage extracellular matrix (1-3). Cell-matrix interactions promote tissue homeostasis and facilitate tissue remodeling (4). Disruption of this extracellular matrix, leading to the consistent loss of proteoglycans, results in degenerative changes in cartilage. CD44, through its interaction with actinbinding proteins, associates with the actin network (5,6). Also, a pool of CD44 is associated with lipid rafts; palmitoylation of 2 cysteine residues in CD44 is required for lipid raft association and, concomitantly, is a determinant of the rate of CD44 turnover from the cell surface (7). Therefore, in addition to chondrocyte integrins, CD44 represents another class of receptors that can participate in matrix-cell-cytoskeleton interact...

A 34-year-old Japanese woman developed spiking fever, splenomegaly, arthritis, neutrophilia, hyperferritinaemia (22517 ng/ml), elevated C-reactive protein (9.1 mg/ml) and severe thrombocytopenia (1.7 x 10(4)/microl). The patient had depressed antithrombin III activity and abnormally high concentrations of both fibrin degradation products and thrombin-antithrombin complexes. This condition was resistant to high-dose prednisolone therapy (120 mg/day) and non-steroidal anti-inflammatory drugs. We initiated oral methotrexate therapy (7.5 mg/week, orally) with a favourable outcome. The patient's spiking fever subsided on the first day of methotrexate administration. Elevated levels of ferritin and C-reactive protein in the sera rapidly normalised. Methotrexate rapidly improved the disease state which suggested that methotrexate act via modulation of cytokine production or secretion.

Background: Preventing recurrent pressure injuries (RPIs) is one of the important challenges faced in healthcare, but the risk factors of RPIs have not been fully revealed. This study aims to explore factors associated with RPIs, by focusing on skin physiology and its microbiome as local factors crucial for the health of healed tissue after pressure injury healing. Methods: This prospective observational study was conducted in a long-term care facility in Japan with patients whose PIs had healed within 1 month. Skin physiology was evaluated by stratum corneum (SC) hydration, pH, and transepidermal water loss. Skin bacteria was collected by tape stripping, followed by 16S ribosomal RNA-based metagenomics analysis. These parameters were evaluated every two weeks over a period of six weeks. Results: A total of 30 patients were included in this study, and 8 patients (26.7%) had an RPI within 6 weeks. In this study, significantly lower SC hydration and a higher rate of Staphylococcus species on the healed site were found in the RPI group. Discussion: A high rate of RPIs (about one in four) points out the necessity of a further care strategy on the healed PIs. Lower skin hydration and/or the increase in Staphylococcus bacteria may have a potential to be used as a biomarker for the prediction of RPIs, or may be an intervention point for the prevention of RPIs by, for example, skin cleansing with moisturizing care.