W. de Jager

CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis.

This study investigates the role of CD4+CD25+ regulatory T cells during the clinical course of juvenile idiopathic arthritis (JIA). Persistent oligoarticular JIA (pers-OA JIA) is a subtype of JIA with a relatively benign, self-remitting course while extended oligoarticular JIA (ext-OA JIA) is a subtype with a much less favorable prognosis. Our data show that patients with pers-OA JIA display a significantly higher frequency of CD4+CD25bright T cells with concomitant higher levels of mRNA FoxP3 in the peripheral blood than ext-OA JIA patients. Furthermore, while numbers of synovial fluid (SF) CD4+CD25bright T cells were equal in both patient groups, pers-OA JIA patients displayed a higher frequency of CD4+CD25int T cells and therefore of CD4+CD25total in the SF than ext-OA JIA patients. Analysis of FoxP3 mRNA levels revealed a high expression in SF CD4+CD25bright T cells of both patient groups and also significant expression of FoxP3 mRNA in the CD4+CD25int T cell population. The CD4+CD25bright cells of both patient groups and the CD4+CD25int cells of pers-OA JIA patients were able to suppress responses of CD25neg cells in vitro. A markedly higher expression of CTLA-4, glucocorticoid-induced TNFR, and HLA-DR on SF CD4+CD25bright T regulatory (Treg) cells compared with their peripheral counterparts suggests that the CD4+CD25+ Treg cells may undergo maturation in the joint. In correlation with this mature phenotype, the SF CD4+CD25bright T cells showed an increased regulatory capacity in vitro compared with peripheral blood CD4+CD25bright T cells. These data suggest that CD4+CD25bright Treg cells play a role in determining the patient’s fate toward either a favorable or unfavorable clinical course of disease.

Local Atherosclerotic Plaques Are a Source of Prognostic Biomarkers for Adverse Cardiovascular Events

Objective—Atherosclerotic cardiovascular disease is a major burden to health care. Because atherosclerosis is considered a systemic disease, we hypothesized that one single atherosclerotic plaque contains ample molecular information that predicts future cardiovascular events in all vascular territories. Methods and Results—AtheroExpress is a biobank collecting atherosclerotic lesions during surgery, with a 3-year follow-up. The composite primary outcome encompasses all cardiovascular events and interventions, eg, cardiovascular death, myocardial infarction, stroke, and endovascular interventions. A proteomics search identified osteopontin as a potential plaque biomarker. Patients undergoing carotid surgery (n=574) served as the cohort in which plaque osteopontin levels were examined in relation to their outcome during follow-up and was validated in a cohort of patients undergoing femoral endarterectomy (n=151). Comparing the highest quartile of carotid plaque osteopontin levels with quartile 1 showed a hazard ratio for the primary outcome of 3.8 (95% confidence interval, 2.6–5.9). The outcome did not change after adjustment for plaque characteristics and traditional risk factors (hazard ratio, 3.5; 95% confidence interval, 2.0–5.9). The femoral validation cohort showed a hazard ratio of 3.8 (95% confidence interval 2.0 to 7.4) comparing osteopontin levels in quartile 4 with quartile 1. Conclusion—Plaque osteopontin levels in single lesions are predictive for cardiovascular events in other vascular territories. Local atherosclerotic plaques are a source of prognostic biomarkers with a high predictive value for secondary manifestations of atherosclerotic disease.

Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammation

OBJECTIVE To study the expression levels and immunostimulatory capacities of interleukin-7 (IL-7) in primary Sjögrens syndrome. METHODS Labial salivary gland (LSG) IL-7 expression was determined by immunohistochemistry, using a quantitative scoring system, in 30 patients with sicca syndrome: 15 patients with primary Sjögrens syndrome (SS) and 15 patients with non-SS sicca syndrome. The correlation of IL-7 expression in LSGs with parameters of local and peripheral disease was studied, and serum and salivary IL-7 levels were determined. Additionally, the effects of IL-7 on cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with primary SS were determined in vitro by Luminex multicytokine assay and compared with the effects in control subjects. RESULTS The expression of IL-7 in LSGs was higher in patients with primary SS compared with that in patients with non-SS sicca syndrome. IL-7 was observed primarily in the vicinity of lymphocytic infiltrates. Salivary IL-7 levels in patients with primary SS were higher than those in control subjects. In all 30 patients with sicca syndrome, IL-7 expression in LSGs correlated with parameters of both local and peripheral disease. Furthermore, IL-7 stimulated T cell-attracting and T cell-differentiating cytokines (monokine induced by interferon-gamma [IFNgamma], IFNgamma-inducible 10-kd protein, IL-12, and IL-15), as well as Th1 (IFNgamma), Th2 (IL-4), Th17 (IL-17A), proinflammatory (tumor necrosis factor alpha and IL-1alpha), and regulatory (IL-10 and IL-13) cytokine production by PBMCs. All of these cytokines were previously shown to be associated with primary SS. The IL-7-induced increase in IL-10 production in patients with primary SS was reduced compared with that in control subjects. CONCLUSION The correlation between LSG IL-7 expression and (local) disease parameters in primary SS as well as the IL-7-mediated induction of inflammatory cytokines indicate that IL-7 might contribute to the immunopathology of primary SS.

Low-grade adipose tissue inflammation in patients with mild-to-moderate chronic obstructive pulmonary disease

BACKGROUND Low-grade systemic inflammation is common in chronic obstructive pulmonary disease (COPD), but its source remains unclear. Adipose tissue is a potent producer of inflammatory mediators and may contribute to systemic inflammation in COPD, possibly via hypoxia. OBJECTIVE We studied the influence of COPD and exercise-induced oxygen desaturation on adipose tissue inflammation (ATI) and its contribution to systemic inflammation. DESIGN Subcutaneous adipose tissue biopsies were investigated in 28 clinically stable COPD patients [forced expiratory volume in 1 s: 58 ± 16% predicted; BMI (in kg/m(2)): 24.9 ± 2.9] and 15 age-, sex-, and body composition-matched healthy control subjects. Fat mass was measured with dual-energy X-ray absorptiometry. Patients were prestratified by oxygen desaturation assessed by incremental cycle ergometry. The adipocyte size and adipose tissue expression of 19 inflammatory and hypoxia-related genes were measured, and adipose tissue macrophages (ATMs) were histologically quantified. Systemic inflammatory markers included C-reactive protein (CRP) and a panel of 20 adipokines. RESULTS COPD patients had comparable fat mass but higher CRP and HOMA-IR than did control subjects. COPD patients and control subjects had comparable adipose tissue gene expression, adipocyte size, ATM infiltration, and systemic adipokine concentrations. Desaturating COPD patients had no different ATI status than did nondesaturating COPD patients. COPD patients with high CRP had significantly greater ATM infiltration than did patients with low CRP, which was independent of BMI and fat mass. CONCLUSIONS In COPD patients, mild-to-moderate COPD, per se, does not enhance ATI or its contribution to systemic inflammation compared with in well-matched healthy control subjects. However, to our knowledge, our study provides a first indication for a possible role of ATMs in the systemic inflammatory response in COPD that requires additional investigation. This trial was registered at www.trialregister.nl as NTR1402.

Treatment-specific changes in circulating adipocytokines: a comparison between tumour necrosis factor blockade and glucocorticoid treatment for rheumatoid arthritis.

Objective There is increasing evidence that adipocytokines may exert proinflammatory and destructive effects in rheumatoid arthritis (RA). Hence, the authors investigated the relationship between adipocytokines and several features associated with RA (inflammation, joint destruction and cardiovascular disease), as well as the effect of treatment with a tumour necrosis factor inhibitor or glucocorticoids (GCs) hereupon. Methods Serum levels of adiponectin, leptin, resistin, visfatin, vaspin and lipids were determined in a well-defined cohort of patients with RA before and after 16 weeks of adalimumab treatment (adalimumab cohort). The same parameters were analysed in two other cohorts of patients with RA before and after 2 weeks of high-dose prednisolone (high GC cohort) and before and after 22 weeks of treatment with a combination regimen with tapered high-dose prednisolone (COBRA -GC cohort). Radiographs of hands and feet (adalimumab and COBRA-GC cohorts) were assessed at baseline and after treatment. Results Treatment with adalimumab or GC showed opposing effects on vaspin and visfatin levels. Lipid levels improved after several months of adalimumab or GC treatment; in the adalimumab cohort, this was related to reduced visfatin levels, independent of C reactive protein levels. After long-term adalimumab or GC treatment, resistin levels declined, which was associated with a decrease in inflammation markers. In the adalimumab cohort, baseline resistin levels were predictive of baseline radiological damage, independent of anticitrullinated peptide antibodies status or C reactive protein levels. Conclusion Changes in serum adipocytokine levels were treatment specific, further strengthening the role of visfatin and resistin in several disease manifestations of RA.

Effectiveness of first line use of recombinant IL-1RA treatment in steroid naïve systemic juvenile idiopathic arthritis: Results of a prospective cohort study

To conduct a prospective cohort study using anakinra, a recombinant IL‐1 receptor antagonist (IL‐1Ra), as first‐line therapy in patients with new‐onset systemic juvenile idiopathic arthritis (JIA).

Cytokine profiles in multifocal motor neuropathy and progressive muscular atrophy.

Multifocal motor neuropathy (MMN) and progressive muscular atrophy (PMA) are associated with IgM monoclonal gammopathy or the presence IgM anti-GM1-antibodies. To further investigate the pathophysiology of MMN and PMA we determined concentrations of 16 mainly B-cell associated inflammatory markers in serum from 25 patients with MMN, 55 patients with PMA, 25 patients with amyotrophic lateral sclerosis (ALS) and 50 healthy controls. Median serum concentrations of the 16 tested cytokines and chemokines were not significantly increased in patients with MMN or patients with PMA, irrespective of the presence of IgM monoclonal gammopathy or high IgM anti-GM1 antibodies. These results argue against a systemic B-cell mediated immune response underlying the pathogenesis of MMN and PMA.

Akinra restores the defective IL-18 NK cell axis in steroid naïve systemic onset JIA patients

Systemic Onset Juvenile Idiopathic Arthritis (SoJIA) is characterized by systemic inflammation and chronic arthritis. Intriguingly, the IL-18-NK cell axis seems to be disturbed in the majority of SoJIA patients. The observed NK cell dysfunction in SoJIA patients contributes to important features of the disease including the susceptibility for macrophage activation syndrome. Here we describe the effects of Anakinra mono treatment on the IL-18-NK cel axis in steroid naive SoJIA patients. In this study sixteen consecutive patients diagnosed with systemic onset JIA were included. Clinical response to Anakinra was evaluated using the validated core set parameters for JIA as well as several biochemical parameters of disease activity. In this cohort we show a good clinical response to Anakinra in 14/16 patients SoJIA patients prior to standard steroid treatment. After 3 weeks of treatment 75% of patients achieved a pACR90 score. Clinical improvement was accompanied by normalization of IL-1, IL-6 and IL-18 levels in plasma. Interestingly, the use of Anakinra in patients with short disease duration induces restoration of the IL-18 - NK cell axis resulting in improved lytic NK cell function and regaining of the NK cell responsiveness to IL-18 stimulation. Moreover, Anakinra seems to down regulate inflammasome activation. These data suggest that the mechanisms of inflammatory control induced by Anakinra in SoJIA patients involves more than blocking IL-1R signaling, since it seems to restore the IL-18-NK cell route as well.

V1.2. RECOGNITION OF MULTIPLE HSP60 EPITOPES IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS OPENS THE WAY FOR ANTIGEN-SPECIFIC IMMUNOTHERAPY

Objective: We previously showed that in Juvenile Idiopathic Arthritis (JIA) patients human and bacterial heat shock protein 60 can be the target of (autoimmune) T cell responses. To determine potential target epitopes for immunotherapy, we needed to identify hsp60 epitopes recognized by a majority of JIA patients. The polymorphic HLA background in JIA has hampered this before. Methods: With the usage of a novel computeralgorithm (Sette, Eppimmune, La Jolla, CA), predicting potential pan-DR binding sites on a given protein sequence, eight different T cell epitopes on both human and mycobacterial hsp60 have been identified and tested for T cell responses in JIA patients. Results: All eight peptides yielded clear T cell responses (T cell proliferation and cytokine production), each in a majority (60-100%) of JIA patients. Interestingly we found production of TNF-α, IFN-γ and IL-10; the production of both IL-10 and IFN-γ strongly suggests the induction of regulatory T cells. One of the identified mycobacterial epitopes, had only minor changes compared tot the peptide that induced protection in Adjuvant Arthritis, and there was a clear correlation between the T cell response to this mycobacterial peptide and its human analogue. This underlines that we have found a subset of T cells crossreacting between self and non-self hsp60. Conclusion: We have identified eight hsp60 epitopes recognized by a majority of JIA patients. The cytokine response induced by these peptides suggests the induction of regulatory T cells. Further analysis is currently being performed to unravel in detail the nature of the found T cell responses. View this table: Table 4-1 Comparison of MIF –173 C/G allele frequencies (%) in JIA patients vs Controls View this table: Table 8-2 Incidence of vasculitis (95% CI) per 100,000 children/year. *p<0.01 from other ethnic groups # V1.3. HUMAN HSP60 INDUCES REGULATORY T CELLS EXPRESSING CD30 IN THE REMITTING FORM OF JIA {#article-title-2} Of Juvenile Idiopathic Arthritis (JIA) the oligoarticular form has a relative benign clinical course, whereas polyarticular and systemic JIA are non-remitting, …

S100A12 as diagnostic tool in the differential diagnosis of sJIA associated MAS vs. hereditary or acquired HLH

8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases