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... Show moreIntervention 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. Show less
OBJECTIVE:: Recently new classification criteria for Rheumatoid Arthritis (RA) have been devised by methodology that used first a quantitative approach (data from databases), then a qualitative... Show moreOBJECTIVE:: Recently new classification criteria for Rheumatoid Arthritis (RA) have been devised by methodology that used first a quantitative approach (data from databases), then a qualitative approach (consensus-based on paper patients) and finally a common sense based approach (evaluation of the former phases). Now these criteria are being evaluated to assess characteristics of the individual items. This study analyzed characteristics of the item autoantibodies, in particular RF-level. METHODS:: Three separate cohorts with a total of 972 undifferentiated arthritis patients were studied for RA-development (according to the 1987 ACR criteria) and arthritis persistency. Positive and negative predictive values (PPV, NPV) and likelihood ratios (LR) were compared between different levels of RF and the presence of ACPA. A similar comparison was made in 686 RA-patients for the rate of joint destruction during 7 years of follow-up and achievement of sustained-DMARD-free-remission. The variation in RF-levels obtained by different measurement methods in the same RF-positive sera was explored. RESULTS:: Presence of ACPA had a better balance between LR+/LR- and PPV/NPV than high RF-levels for RA-development. The additive value of ACPA assessment after high level RF-testing was higher than vice versa. High level RF was less strongly associated with RA-severity than ACPA-antibodies. The RF-level obtained by different methods in the same patients' sera varied considerably. CONCLUSION:: Level determination of RF is subject to large variation; high level RF has limited additive prognostic value compared to ACPA-positivity. Thus, omitting RF level and using RF-presence, ACPA-presence and ACPA-level may improve the 2010 criteria for RA. Show less
Scherer, H.U.; Woude, D. van der; Ioan-Facsinay, A.; Bannoudi, H. el; Trouw, L.A.; Wang, J.; ... ; Toes, R.E.M. 2010
Objective. Anti-citrullinated protein antibodies ( ACPA) exhibit unique specificity for rheumatoid arthritis. However, it is incompletely understood whether and how ACPA contribute to disease... Show moreObjective. Anti-citrullinated protein antibodies ( ACPA) exhibit unique specificity for rheumatoid arthritis. However, it is incompletely understood whether and how ACPA contribute to disease pathogenesis. The Fc part of human IgG carries 2 N-linked glycan moieties that are crucial for the structural stability of the antibody and that modulate both its binding affinity to Fc gamma receptors and its ability to activate complement. We undertook this study to analyze Fc glycosylation of IgG1 ACPA in serum and synovial fluid ( SF) in order to further characterize the immune response to citrullinated antigens. Methods. ACPA were isolated by affinity purification using cyclic citrullinated peptides as antigen. IgG1 Fc glycosylation was analyzed by mass spectrometry. ACPA IgG1 glycan profiles were compared with glycan profiles of total serum IgG1 obtained from 85 well-characterized patients. Glycan profiles of paired SF and serum samples were available from 11 additional patients. Results. Compared with the pool of serum IgG1, ACPA IgG1 lacked terminal sialic acid residues. In SF, ACPA were highly agalactosylated and lacked sialic acid residues, a feature that was not detected for total SF IgG1. Moreover, differential ACPA glycan profiles were detected in rheumatoid factor (RF)-positive and RF-negative patients. Conclusion. ACPA IgG1 exhibit a specific Fc-linked glycan profile that is distinct from that of total serum IgG1. Moreover, Fc glycosylation of ACPA differs markedly between SF and serum. Since Fc glycosylation directly affects the recruitment of Fc-mediated effector mechanisms, these data could further our understanding of the contribution of ACPA to disease pathogenesis. Show less
Scherer, H.U.; Linden, M.P.M. van der; Kurreeman, F.A.S.; Stoeken-Rijsbergen, G.; Cessie, S. le; Huizinga, T.W.J.; ... ; Toes, R.E.M. 2010
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... Show moreBACKGROUND: /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. Show less
Scherer, H.U.; Linden, M.P.M. van der; Kurreeman, F.A.S.; Stoeken-Rijsbergen, G.; Cessie, S. le; Huizinga, T.W.J.; ... ; Toes, R.E.M. 2010
Background 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... Show moreBackground 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 a-induced protein 3 (TNFAIP3). TNFAIP3 is a negative regulator of NF-kappa B 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 To analyse the effect of the 6q23 region on the rate of joint destruction. Methods 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 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 These data associate the 6q23 region with the rate of joint destruction in ACPA+ RA. Show less
Ioan-Facsinay, A.; Bannoudi, H. el; Scherer, H.U.; Woude, D. van der; Menard, H.A.; Lora, M.; ... ; Toes, R.E.M. 2010
OBJECTIVE:: Anti-citrullinated protein antibodies (ACPA) exhibit unique specificity for RA. Whether and how ACPA contribute to disease pathogenesis, however, is incompletely understood. The Fc part... Show moreOBJECTIVE:: Anti-citrullinated protein antibodies (ACPA) exhibit unique specificity for RA. Whether and how ACPA contribute to disease pathogenesis, however, is incompletely understood. The Fc part of human IgG carries two N-linked glycan moieties which are crucial for the structural stability of the antibody and modulate its binding affinity to Fcgamma receptors and its ability to activate complement. We have purified ACPA from serum and synovial fluid and analyzed Fc glycosylation profiles in a specific manner. METHODS:: ACPA were isolated by affinity purification using cyclic citrullinated peptides as antigen. IgG(1) Fc glycosylation was analyzed by mass spectrometry. ACPA glycan profiles were compared to glycan profiles of total serum IgG(1) obtained from 85 well-characterised patients. Glycan profiles of paired synovial fluid and serum samples were available from 11 additional patients. RESULTS:: Compared to the pool of serum IgG(1), ACPA IgG(1) lack terminal sialic acid residues. In synovial fluid, ACPA are highly agalactosylated and lack sialic acid residues, a feature that was not detected for total synovial fluid IgG(1). Moreover, differential ACPA glycan profiles were detected in RF-positive versus -negative patients. CONCLUSION:: ACPA IgG(1) exhibit a specific Fc-linked glycan profile which is distinct from total serum IgG(1). Moreover, Fc glycosylation of ACPA differs markedly between synovial fluid and serum. As Fc glycosylation directly affects the recruitment of Fc-mediated effector mechanisms, these data could further our understanding of the contribution of ACPA to disease pathogenesis. Show less
