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Activation of the complement system by nanoparticles limits nanomedicine. The co-administration of fused complement inhibitors could largely block complement opsonization and unwanted granulocyte/monocyte uptake, as well as reducing side-effects of bolus-injected nanoparticles.

New insights into the etiology of rheumatoid arthritis have suggested that humoral autoimmunity might have a substantive, possibly even causal role in the pathogenesis of disease. In this Viewpoint, Dr Holers will discuss the basis of this hypothesis, focusing on the role of anti-cyclic citrullinated peptide antibodies.

The presence of antibodies to citrullinated protein antigens (ACPA) in peripheral blood represents a risk a state that is ‘at-risk’ for subsequent development of rheumatoid arthritis (RA). Here authors compare multiple molecular and immunological parameters in individuals who are ACPA positive without inflammatory arthritis, ACPA negative controls and patients diagnosed with ACPA positive early-stage RA to conclude that complex immunopathological processes are present in an ACPA positive state which may be targeted by future preventive approaches for RA.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

Activated B cells and T cells accumulate within joints of patients with rheumatoid arthritis. Here, the authors use single-cell transcriptome and repertoire profiling to identify clonally expanded synovial B cells and T cells and define their phenotypes and predicted cell-cell interactions.

Peter Gregersen and colleagues report that common variants at the REL locus are associated with risk of rheumatoid arthritis. REL encodes a member of the NF-κB family of transcription factors, which play key roles in coordinating immune and inflammatory responses.

Holers and colleagues review current data linking immune mechanisms and dysbiosis at distinct mucosal sites to risk of rheumatoid arthritis (RA). Their newly introduced causal mucosal endotypes hypothesis suggests that lung-, gut-, or oral-associated endotypes might drive the pathogenesis and progression of RA, and highlights associated research directions towards preventive and therapeutic strategies in RA.

Single-cell transcriptomic and proteomic data from synovial tissue from individuals with rheumatoid arthritis classify patients into groups based on abundance of cell states that can provide insights into pathology and predict individual treatment responses.

Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13⁺ T_PH/T_FH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues.

Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.

The immune mechanisms underlying synovitis and joint tissue destruction in rheumatoid arthritis (RA) remain incompletely defined. Here, the authors demonstrate that ACPA+ RA patients have activated clonally expanded cytotoxic GZMB+ CD8+ T cells in blood and synovium that target and are activated by citrullinated antigens to mediate cell killing.

SCENT is a nonparametric method that models association between chromatin accessibility and gene expression in single-cell multimodal datasets, enabling construction of cell-type-specific enhancer–gene maps to aid mapping of candidate causal variants and genes for common diseases.

The epigenetic changes underlying the heterogeneity of RA disease presentation have been the subject of intense scrutiny. In this study, the authors use multiple single-cell sequencing datasets to define ‘chromatin superstates’ in patients with RA, which associate with distinct transcription factors and disease phenotypes.

Automated pathotyping of synovial tissue in arthritis is a major unmet need. Here, the authors develop and demonstrate the efficacy of an automated tissue and cellular pathotyping tool for inflammatory arthritis.

NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.

Immune proteins bind to protein corona on core-shell nanoparticles and undergo dynamic exchange in vivo.

Defining cell types and their activation status in rheumatoid arthritis (RA) is critical to understanding this disease. Raychaudhuri and colleagues leverage several single-cell -omics approaches to define the cellular processes and pathways in the human RA joint.

This Review provides an overview of the complement system and its role in a range of rheumatic and autoimmune diseases, and examines the rapidly expanding landscape of complement therapeutics in these settings, as well as prospects for improving their clinical use.

Preclinical rheumatoid arthritis (RA) is characterized by the presence of RA-related autoantibodies in the serum in the absence of clinical symptoms. This Review discusses the relationships during this period between mucosal alterations and the initiation of local and systemic anti-citrullinated protein antibody production.

scHLApers is an analysis pipeline that quantifies single-cell expression of HLA genes using a personalized genomic reference. Mapping of HLA expression quantitative trait loci at single-cell resolution identifies dynamic effects across cell states.

Immunoglobulin A (IgA) has two subclasses, IgA1 and IgA2, but differential effects on inflammation are unclear. Here the authors show that IgA2, when compared with IgA1, has stronger pro-inflammatory functions associated with changed glycosylation and higher disease scores in patients with rheumatoid arthritis.

Therapeutic innovations of potentially great clinical impact should embrace the overarching values of research accountability, data transparency and validation through the scientific peer-review process.

Osteoarthritis, the breakdown of cartilage in synovial joints, has long been viewed as the result of 'wear and tear', but this report shows that dysregulation of the complement system has an active role in the pathogenesis of this disease.

Childhood-onset arthritis has historically been treated as a separate entity to adult-onset arthritis, with its own nomenclature and classification system. Biological evidence has revealed the limitations of the current approach, necessitating a fresh look at the classification of paediatric arthritis.