Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2

To assess the role of angiopoietin (Ang)-1 and Ang-2 and to investigate the clinical significance of serum levels of them in systemic juvenile idiopathic arthritis (s-JIA)-associated macrophage activation syndrome (MAS), we determined these levels in 51 patients with s-JIA, 11 patients with polyarticular JIA (poly-JIA), 12 patients with virus associated hemophagocytic syndrome (VAHS), 12 patients with Kawasaki disease (KD), and 15 age-matched healthy controls (HC). The results were compared with clinical features of MAS. During the MAS phase, serum Ang-1 levels were significantly decreased compared with those during the active and inactive phases. Serum Ang-2/1 ratio were significantly elevated during the MAS phase, compared with those during the active and inactive phases. There was a rapid increase in the Ang-2/1 ratio at the onset of MAS. Serum Ang-1 and the Ang-2/1 ratio significantly correlated with measures of disease activity, including AST and LDH. Ang-2/1 dysregulation was also observed in patients with VAHS, whereas not observed in most cases of KD. The homeostasis of vascular endothelial function by Ang-1 and Ang-2 is disrupted in MAS. Serum Ang-1 levels and the Ang-2/1 ratio might represent promising indicators of disease activity for MAS.     

ABO blood group and secretor status in the spondyloarthropathies

Abstract The postulated role of infectious agents, genetic susceptibility of the host to infection and their interaction in the pathogenesis of ankylosing spondylitis, other spondyloarthropathies, and the associated primary (non-arthritic) diseases are reviewed.
Compared with a local control population there is a significantly increased prevalence of non-secretors amongst different groups of patients with spondyloarthropathy: ankylosing spondylitis, reactive arthritis and psoriatic arthropathy. No differences between secretor and non-secretor patients with respect to serum and salivary IgA levels, the occurrence of eye lesions or peripheral joint disease have been found. There is no evidence that ankylosing spondylitis or other spondyloarthropathies are associated with any particular ABO blood group.
The association between non-secretion and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis has an infective aetiology. It also suggests several pathogenetic mechanisms which may be relevant to the initial host-parasite interactions in the spondyloarthropathies.     

Heat shock proteins as potential targets in the therapy of inflammatory arthritis

Whether heat shock proteins (hsp) will be therapeutic targets in arthritis depends on their role in pathogenesis. In this article, three possibilities are considered. Firstly, an excessive immune response to bacterial hsp could be arthritogenic — as may occur in reactive arthritis. In these circumstances therapy would be directed to down-regulating this immune response, or altering the nature of the immune response e.g. by changing cytokine production from interferon-g to IL-4. However this approach depends on the immune response to bacterial hsp not being critical for control of the bacterial infection. Secondly, an immune response to bacterial hsp may induce autoimmunity by cross-reactivity, e.g. with the homologous human. This could also be modulated in the same way with a lower likelihood of interfering with control of the infectious agent, since only a component of the immune response against the bacterial hsp will be cross-reactive with self. Thirdly, recent experiments raise the possibility that joint inflammation might be controlled by T cells which recognizes self hsp, particularly hsp60. Therapies might enhance this response; protection from experimental arthritis by prior immunization with hsp60 is well established. Whether similar approaches will be viable after arthritis is established remains to be seen.     

THE FUNDAMENTALS OF PHARMACOPHORE MODELING IN COMBINATORIAL CHEMISTRY*

Abstract

Objective: To better understand the risks of rheumatoid arthritis (RA) and certain subsets conferred by mannose-binding lectin (MBL2) polymorphisms in different races. Materials and methods: Eighteen articles (4810 cases and 4585 controls) were identified from the latest literature search carried out in May 2014 using PubMed, Web of Science, Wanfang Database (Chinese) and Chinese National Knowledge Infrastructure. Three single nucleotide polymorphisms of codon 52, 54 and 57, exonic and extended genotypic variance in MBL2 were synthesized. Results: Codon 54 mutation of MBL2 was unlikely to be a risk factor for RA in overall population, but turned out to be deleterious in East Asian (four studies with 523 cases and 647 controls, pooled OR:1.63, 95% CI: 1.23–2.17). Codon 54 mutation increased the risk of seropositive and erosive RA by 44% and 162%, respectively (three studies with 281 cases and 358 controls, 95% CI: 1.01–2.05; 3 studies with 180 cases and 499 controls, 95% CI: 1.77–3.88). Furthermore, those risks were relatively stronger when restricted in East Asian (two studies with 147 cases and 244 controls, pooled OR: 1.85, 95% CI: 1.19–2.87; 2 studies with 170 cases and 291 controls, pooled OR: 2.78, 95% CI: 1.85–4.20). No remarkable associations were detected regarding codon 52, 57, exon 1 and extended genotype of MBL2. Conclusions: Polymorphism of codon 54 in MBL2 may predispose to RA, especially seropositive or erosive RA, which East Asian appears to be more vulnerable.     

Synovial Mononuclear Cells Consist with T Cells Which Produce High Levels of Tumor Necrosis Factor α

To determine whether synovial mononuclear cells include a population of tumor necrosis factor α-produeing T cells, we measured tumor necrosis α levels in culture supernatants of synovial mononuclear cells by ELISA and analyzed tumor necrosis α mRNA-positive cell frequencies. There were no significant differences in the spontaneous levels of TNF α between synovial mononuclear cells and peripheral mononuclear cells. The frequency of tumor necrosis factor α mRNA-positive cells in synovial mononuclear cells was higher than that of peripheral mononuclear cells. When stimulated with a superantigen, mononuclear cells from the synovial fluid of rheumatoid arthritis patients showed higher levels of tumor necrosis factor α production (1,035 ± 817 pg/ml) than did mononuclear cells from their peripheral blood (236 ± 180 pg/ml). In addition, we observed that a few T cell clones were resistant to superantigenic restimulation in vitro. We conclude that when these types of T cells persist in the synovium, they play a role in the development of rheumatoid arthritis via a mechanism involving tumor necrosis factor α production.     

Nasal administration of arthritis-related T cell epitopes of heat shock protein 60 as a promising way for immunotherapy in chronic arthritis

Adjuvant Arthritis (AA) can be induced in Lewis rats by immunisation with mycobacterial antigens. The disease can be passively transferred with T cell clone A2b, which recognises the 180–188 amino acid sequence in mycobacterial heat shock protein 60 (hsp60) and which crossreacts with crude cartilage proteoglycans. We succeeded to induce peripheral tolerance to this AA-associated T cell epitope following nasal administration of a peptide containing this epitope (mycobacterial hsp60 176–190). In rats treated nasally with 176–190 and immunised with mycobacterial hsp60, proliferative responses to 176–190 were reduced. AA was inhibited nasally with 176–190 treated rats and not in rats nasally treated with a control mycobacterial hsp60 peptide (211–225). Moreover, nasal 176–190 led to similar arthritis protective effects in a non-microbially induced experimental arthritis (avridine induced arthritis). In a subsequent study we tried to prevent and to treat AA through nasal administration of mycobacterial hsp60 peptide 180–188 and a peptide analogue of 180–188, 180–188_L183->A (Alanine 183), which has been shown to have an increased MHC-binding affinity for rat RT1 B¹ and an increased capacity to inhibit the proliferative A2b responsein vitro. We found that nasal administration of 180–188 had a moderate arthritis suppressive effect in AA, whereas its analogue peptide Alanine 183, had a strong suppressive effect. This strong arthritis suppressive effect was only partly due to the higher MHC-binding affinity for rat RT1 B¹. Furthermore, it was possible to passively transfer nasal Alanine 183 induced disease protection. The present findings may in our view offer novel prospects for immunotherapy through nasal administration of (analogue) peptides, with a mimicry relationship with joint specific cartilage proteoglycan epitopes.     

Crystallization and preliminary X-ray diffraction studies of the cartilage link protein from bovine trachea

Cartilage extracellular matrix link protein, having molecular mass of approximately 40 kDa, is a metalloprotein that binds divalent cations and is only soluble in low ionic strength solutions. The link protein was purified from bovine trachea and has been crystallized by a vapor diffusion method using PEG 3350 as precipitant. The crystal symmetry is P1, and the unit cell dimensions are a = 43.55, b = 53.11, c = 60.10 Å, α = 90.44, β = 106.21, γ = 101.51°. The V_M of 1.8 Å₃/Da is consistent with the presence of two molecules of the link protein in the asymmetric unit. The crystals diffract X-rays from a synchrotron source to 1.7 Å resolution. © 1995 Wiley-Liss, Inc.     

Announcement

We are pleased to announce a number of changes to the journal that will take effect from the start of 2003.