Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1β (IL-1β)–stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS–dominant (invasive), and RA-SM–dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix–loop–helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1β. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1β. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.

Fibroblast-like synoviocytes mediate joint destruction in rheumatoid arthritis and exhibit sustained proinflammatory and invasive properties. CD44 is a polymorphic transmembrane protein with defined roles in matrix interaction and tumor invasion that is also a signaling coreceptor for macrophage migration inhibitory factor (MIF), which engages cell surface CD74. High-expression MIF alleles (rs5844572) are associated with rheumatoid joint erosion, but whether MIF signaling through the CD74/CD44 receptor complex promotes upstream autoimmune responses or contributes directly to synovial joint destruction is unknown. We report here the functional regulation of CD44 by an autocrine pathway in synovial fibroblasts that is driven by high-expression MIF alleles to up-regulate an inflammatory and invasive phenotype. MIF increases CD44 expression, promotes its recruitment into a functional signal transduction complex, and stimulates alternative exon splicing, leading to expression of the CD44v3-v6 isoforms associated with oncogenic invasion. CD44 recruitment into the MIF receptor complex, downstream MAPK and RhoA signaling, and invasive phenotype require MIF and CD74 and are reduced by MIF pathway antagonists. These data support a functional role for high-MIF expression alleles and the two-component CD74/CD44 MIF receptor in rheumatoid arthritis and suggest that pharmacologic inhibition of this pathway may offer a specific means to interfere with progressive joint destruction.immunogenetics | autoimmunity | MIF | CD44 | CD74

Microbial habitation in the human body begins immediately after birth, and adults are colonized by microbes outnumbering human cells by a factor of ten. Especially, intestinal track is a living space for diverse microbial species that have coevolved symbiotically. A principal function of the gut microbiota is to protect the host from harmful bacteria and to provide benefits for the host through several mechanisms, including direct competition for limited nutrients, training of host immune systems to recognize specifically foreign materials and conversion of otherwise indigestible food into energy and absorbable nutrients. Therefore, gut dysbiosis, a bacterial imbalance state, is related with the pathogenesis of various host diseases including autoimmune diseases. In the current review, we highlight the importance of gut microbiota in the normal health and autoimmune diseases. We also discuss regulation of gut dysbiosis and future direction for potential clinical applications, including treatment and diagnostics of autoimmune diseases.

Psoriasis is a chronic inflammatory skin disorder mediated by the T-cell–related immune response. Psoriatic patients may have a variety of comorbidities, but their risk of end-stage renal disease (ESRD), particularly according to the subtype of psoriasis, is unclear. We investigated the risk of ESRD in patients with psoriasis according to the subtype of psoriasis and history of systemic therapy for psoriasis. A total of 2,121,228 adults (1,590,921 in the control group and 530,307 in the psoriasis group) were enrolled in this nationwide population-based cohort study until 2015. During follow-up, 1,434 of the subjects in the psoriasis group developed ESRD. After adjusting for confounding factors, psoriasis was associated with the risk of ESRD (hazard ratio (HR) 1.58, 95% confidence interval [95% CI] 1.47–1.68). The psoriatic arthritis group (HR 7.60, 95% CI 1.90–30.41) had a higher risk of ESRD than the control group. Interestingly, no such association was detected in the systemically treated group (HR 1.07, 95% CI 0.80–1.41). Moreover, the acitretin-treated group had a lower risk of ESRD (HR 0.658, 95% CI, 0.494–0.875) than the non-systemically treated group. In conclusion, the risk of developing ESRD in patients with psoriasis differed according to the type of treatment and the presence of arthritis.