Objective. The Sa autoantigen can be found in inflamed synovium of patients with rheumatoid arthritis (RA), and at least part of the humoral RA-specific anti-Sa response is directed against citrullinated vimentin. This study was undertaken to evaluate the sensitivity, specificity, and prognostic value of determination of levels of antibodies against modified citrullinated vimentin (anti-MCV) as compared with antibodies against cyclic citrullinated peptides (anti-CCP) in an inception cohort of patients with early RA.Methods. Clinical data, radiographs, and measurements of levels of anti-MCV and anti-CCP antibodies were obtained in 273 patients with early RA at baseline, after 3 months, and after 1, 2, 3, and 5 years. Autoantibodies were also analyzed in 100 healthy controls. Conclusion. These findings show that when patients with early RA are compared with healthy controls, analysis of anti-MCV yields greater sensitivity and unchanged specificity as compared with analysis of anti-CCP. Anti-MCV also appears to perform better than anti-CCP in identifying poor radiographic prognosis in patients with early RA. Results

Conclusion. Development of an immune response toward citrullinated peptides is initially restricted but expands with time to induce a more specific response, with levels, particularly those of antibodies against CEP-1, Fib␤36-52, and filaggrin, increasing during the predating time period closer to the onset of symptoms.

Rheumatoid factor is strongly associated with severe ExRA manifestations in patients with rheumatoid arthritis, and a similar but weaker association exists for anti-CCPs. This suggests a role for rheumatoid factor and anti-CCP in the pathogenesis of ExRA.

IntroductionAutoantibodies directed against citrullinated proteins/peptides (ACPAs) are highly specific and predictive for the development of rheumatoid arthritis (RA). Different subgroups of RA patients, which have different prognoses and may require different treatments, are characterized by different autoantibody profiles. The objective of this study was to develop a microarray for the detection of multiple RA-associated autoantibodies, initially focusing on responses against citrullinated epitopes on candidate autoantigens in RA.MethodsThe microarray is based on Phadia's ImmunoCAP ISAC system, with which reactivity to more than 100 antigens can be analyzed simultaneously, by using minute serum volumes (< 10 μl). Twelve citrullinated peptides, and the corresponding native arginine-containing control peptides, were immobilized in an arrayed fashion onto a chemically modified glass slide, allowing a three-dimensional layer with high binding capacity. The assay was optimized concerning serum dilution and glass surface, whereas each individual antigen was optimized concerning coupling chemistry, antigen concentration, and selection of spotting buffer. The performance of each peptide in the ImmunoCAP ISAC system was compared with the performance in enzyme-linked immunosorbent assays (ELISAs). Serum from 927 RA patients and 461 healthy controls from a matched case-control study were applied onto reaction sites on glass slides, followed by fluorescent-labeled anti-human immunoglobulin G (IgG) antibody. Fluorescence intensities were detected with a laser scanner, and the results analyzed by using image-analysis software.ResultsStrong correlations between the ImmunoCAP ISAC system and ELISA results were found for individual citrullinated peptides (Spearman ρ typically between 0.75 and 0.90). Reactivity of RA sera with the peptides was seen mainly in the anticyclic citrullinated peptide 2 (CCP2)-positive subset, but some additional reactivity with single citrullinated peptides was seen in the anti-CCP2-negative subset. Adjusting for reactivity against arginine-containing control peptides did not uniformly change the diagnostic performance for antibodies against the individual citrullinated peptides.ConclusionsThe multiplexed array, for detection of autoantibodies against multiple citrullinated epitopes on candidate RA autoantigens, will be of benefit in studies of RA pathogenesis, diagnosis, and potentially as a guide to individualized treatment.

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Objective. Interferon-␣ (IFN␣) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFN␣ production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated.Methods. Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFN␣ production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E 2 (PGE 2 ), reactive oxygen species (ROS), or the cytokines IFN␣2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor ␣ (TNF␣) were explored.Results. Monocytes inhibited IFN␣ production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFN␣ production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFN␣2b/GM-CSF increased their IFN␣ production. RNA-containing ICs caused production of ROS, PGE 2 , and TNF␣, especially in monocytes. These mediators and IL-10 suppressed IFN␣ production in PBMC cultures, with ROS and PGE 2 also inhibiting IFN␣ production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFN␣2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase.Conclusion. IFN␣ production induced by RNAcontaining ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro-and antiinflammatory molecules. This should be considered when designing and applying new therapies.

Self-rated health is a powerful and independent predictor of long-term health, but its biological basis is unknown. We have shown previously that self-rated health is associated with increased levels of circulating cytokines in women. The main aim of the present study was to increase the understanding of the association between markers of wellbeing, such as self-rated health, and cytokines and to investigate the impact of age on these associations. In 174 female consecutive primary health care patients divided into three age groups, we examined subjective ratings of health and aspects of wellbeing and circulating levels of IL (interleukin)-1beta, IL-1ra (IL-1 receptor antagonist), IL-6 and TNF-alpha (tumour necrosis factor-alpha). Poor self-rated health was significantly associated with higher levels of TNF-alpha in all of the age groups. For IL-1beta and IL-1ra, the correlations with self-rated health were significant only in the oldest age group. Lower ratings of other measurements of health and wellbeing were related to higher levels of cytokines, most pronounced for TNF-alpha and IL-1beta, and in the middle and olderst age groups. More symptoms resembling a sickness response induced by inflammation were implicated to be associated with lower self-rated health. The strength of the association between inflammatory cytokines and poor health perception increased with advanced age, indicating an increased vulnerability for inflammatory activity during aging. It is suggested that higher levels of TNF-alpha are connected to a sickness response that, in turn, is connected to self-rated health. The results provide a possible psychobiological basis to understand better diffuse subjective symptoms and poor subjective health in women.

Objective. Type II collagen (CII) is a major component of hyaline cartilage, and antibodies against CII are found in a subgroup of patients with rheumatoid arthritis. We undertook this study to investigate whether and how antibodies directed against CII can form solid-phase immune complexes (ICs) with cytokine-inducing properties in a model theoretically resembling the situation in the inflamed joint, in which CII is exposed for interaction with anti-CII antibodies during periods of inflammation.Methods. Sixty-five arthritis patients with varying levels of anti-native CII antibodies and 10 healthy controls were evaluated concerning anti-CII and cytokines induced in a solid-phase IC model. Monocytes were either depleted or enriched to define responder cells. Antibodies blocking Fc␥ receptors (Fc␥R) were used to define the responsible T cell surface receptors.Results. ICs containing anti-CII from arthritis patients induced the production of tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), and IL-8. We found a close correlation between enzyme-linked immunosorbent assay optical density values and induction of TNF␣ (r ‫؍‬ 0.862, P < 0.0001), IL-1␤ (r ‫؍‬ 0.839, P < 0.0001), and IL-8 (r ‫؍‬ 0.547, P < 0.0001). The anti-CIIcontaining IC density threshold needed for cytokine induction differed among peripheral blood mononuclear cell donors. Anti-CII-containing IC-induced cytokine production was almost totally abolished (>99%) after monocyte depletion, and receptor blocking studies showed significant decreases in the production of TNF␣, IL-1␤, and IL-8 after blocking Fc␥RIIa, but not after blocking Fc␥RIII.Conclusion. These findings represent a possible mechanism for perpetuation of joint inflammation in the subgroup of arthritis patients with high levels of anti-CII. Blockade of Fc␥RIIa and suppression of synovial macrophages are conceivable treatment options in such patients.Collagen fibrils are structural tissue proteins. Among more than 15 different types of collagens that have been identified in different tissues of vertebrates, type I, II, and III collagens are most abundant in the body. Type II collagen (CII) is the predominant collagen in joint cartilage, constituting Ͼ50% of its dry weight (1).Electron microscopy studies have shown that a