Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases

Integration of gene ontology pathways with North American Rheumatoid Arthritis Consortium genome-wide association data via linear modeling

We describe an empirical Bayesian linear model for integration of functional gene annotation data with genome-wide association data. Using case-control study data from the North American Rheumatoid Arthritis Consortium and gene annotation data from the Gene Ontology, we illustrate how the method can be used to prioritize candidate genes for further investigation

Inflammation functions as a key mediator in the link between ACPA and erosion development: An association study in Clinically Suspect Arthralgia

Background: Anti-citrullinated protein antibodies (ACPA) are associated with more severe joint erosions in rheumatoid arthritis (RA), but the underlying mechanism is unclear. Recent in vitro and murine studies indicate that ACPAs can directly activate osteoclasts leading to bone erosions and pain. This study sought evidence for this hypothesis in humans and evaluated whether in patients with arthralgia who are at risk of RA, ACPA is associated with erosions (detected by magnetic resonance imaging (MRI)) independent of inflammation, and also independent of the presence of rheumatoid factor (RF). Methods: Patients with Clinically Suspect Arthralgia (n = 507) underwent determination of ACPA and RF and 1.5 T contrast-enhanced MRI of the metacarpophalangeal, wrist and metatarsophalangeal joints at baseline. MRIs were scored for presence of local inflammation and erosions. Comparisons of erosion scores were performed using the Kruskal-Wallis test. To evaluate if inflammation is, in statistical terms, intermediary in the causal path of ACPA and erosions, three-step mediation analysis was performed using linear regression. Results: ACPA-positive patients had higher erosion scores than ACPA-negative patients (p = 0.006). ACPA-positive patients without subclinical inflammation did not have higher erosion scores than ACPA-negative patients (p = 0.68), in contrast to ACPA-positive patients with local inflammation (p < 0.001). Mediation analyses suggested that local inflammation is in the causal path of ACPA leading to higher erosion scores. Compared to ACPA-negative/RF-negative patients, ACPA-positive/RF-negative patients did not differ (p = 0.30), but ACPA-positive/RF-positive patients had higher erosion scores (p = 0.006). Conclusions: The effect of ACPA on erosions is mediated by inflammation and is not independent of RF

Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics

The healthy synovial lining layer consists of a single cell layer that regulates the transport between the joint cavity and the surrounding tissue. It has been suggested that abnormalities such as somatic mutations in the p53 tumor-suppressor gene contribute to synovial hyperplasia and invasion in rheumatoid arthritis (RA). In this study, expression of epithelial markers on healthy and diseased synovial lining tissue was examined. In addition, we investigated whether a regulated process, resembling epithelial to mesenchymal transition (EMT)/fibrosis, could be responsible for the altered phenotype of the synovial lining layer in RA. Synovial tissue from healthy subjects and RA patients was obtained during arthroscopy. To detect signs of EMT, expression of E-cadherin (epithelial marker), collagen type IV (indicator of the presence of a basement membrane) and α-smooth muscle actin (α-sma; a myofibroblast marker) was investigated on frozen tissue sections using immunohistochemistry. Fibroblast-like synoviocytes (FLSs) from healthy subjects were isolated and subjected to stimulation with synovial fluid (SF) from two RA patients and to transforming growth factor (TGF)-β. To detect whether EMT/fibrotic markers were increased, expression of collagen type I, α-sma and telopeptide lysylhydroxylase (TLH) was measured by real time PCR. Expression of E-cadherin and collagen type IV was found in healthy and arthritic synovial tissue. Expression of α-sma was only found in the synovial lining layer of RA patients. Stimulation of healthy FLSs with SF resulted in an upregulation of α-sma and TLH mRNA. Collagen type I and TLH mRNA were upregulated after stimulation with TGF-β. Addition of bone morphogenetic protein (BMP)-7 to healthy FLS stimulated with SF inhibited the expression of α-sma mRNA. The finding that E-cadherin and collagen type IV are expressed in the lining layer of healthy and arthritic synovium indicates that these lining cells display an epithelial-like phenotype. In addition, the presence of α-sma in the synovial lining layer of RA patients and induction of fibrotic markers in healthy FLSs by SF from RA patients indicate that a regulated process comparable to EMT might cause the alteration in phenotype of RA FLSs. Therefore, BMP-7 may represent a promising agent to counteract the transition imposed on synoviocytes in the RA joint

Association of the 6q23 region with the rate of joint destruction in rheumatoid arthritis

BACKGROUND: /st> Two novel genetic polymorphisms on chromosome 6q23 are associated with susceptibility to rheumatoid arthritis (RA). Both polymorphisms (rs6920220 and rs10499194) reside in a region close to the gene encoding tumour necrosis factor alpha-induced protein 3 (TNFAIP3). TNFAIP3 is a negative regulator of NF-kappaB and is involved in inhibiting TNF-receptor-mediated signalling effects. Interestingly, the initial associations were detected in patients with longstanding RA. However, no association was found for rs10499194 in a Swedish cohort with early arthritis. This might be caused by over-representation of patients with severe disease in cohorts with longstanding RA. OBJECTIVE: /st> To analyse the effect of the 6q23 region on the rate of joint destruction. METHODS: /st> Five single nucleotide polymorphisms in 6q23 were genotyped in 324 Dutch patients with early RA. Genotypes were correlated with progression of radiographic joint damage for a follow-up time of 5 years. RESULTS: /st> Two polymorphisms (rs675520 and rs9376293) were associated with severity of radiographic joint damage in patients positive for anti-citrullinated protein/peptide antibodies (ACPA). Importantly, the effects were present after correction for confounding factors such as secular trends in treatment. CONCLUSIONS: /st> These data associate the 6q23 region with the rate of joint destruction in ACPA+ RA.Pathophysiology and treatment of rheumatic disease

Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte–Induced Apoptosis: Differential Modulation by T Helper Type 1 and Type 2 Cells

Dendritic cells (DCs) play a central role in the immune system as they drive activation of T lymphocytes by cognate interactions. However, as DCs express high levels of major histocompatibility complex class I, this intimate contact may also result in elimination of DCs by activated cytotoxic T lymphocytes (CTLs) and thereby limit induction of immunity. We show here that immature DCs are indeed susceptible to CTL-induced killing, but become resistant upon maturation with anti-CD40 or lipopolysaccharide. Protection is achieved by expression of serine protease inhibitor (SPI)-6, a member of the serpin family that specifically inactivates granzyme B and thereby blocks CTL-induced apoptosis. Anti-CD40 and LPS-induced SPI-6 expression is sustained for long periods of time, suggesting a role for SPI-6 in the longevity of DCs. Importantly, T helper 1 cells, which mature DCs and boost CTL immunity, induce SPI-6 expression and subsequent DC resistance. In contrast, T helper 2 cells neither induce SPI-6 nor convey protection, despite the fact that they trigger DC maturation with comparable efficiency. Our data identify SPI-6 as a novel marker for DC function, which protects DCs against CTL-induced apoptosis