Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis

Expanded populations of CD4+ T cells lacking the co-stimulatory molecule CD28 (CD4+CD28null T cells) have been reported in several inflammatory disorders. In rheumatoid arthritis, increased frequencies of CD4+CD28null T cells in peripheral blood have previously been associated with extra-articular manifestations and human cytomegalovirus (HCMV) infection, but their presence in and contribution to joint manifestations is not clear. In the present article we investigated the distribution of CD4+CD28null T cells in the synovial membrane, synovial fluid and peripheral blood of RA patients, and analysed the association with erosive disease and anti-citrullinated protein antibodies. CD4+CD28null T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-Vβ subsets of CD4+CD28null T cells in peripheral blood were often absent in synovial fluid. CD4+CD28null T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease. Together these data imply a primary role for CD4+CD28null T cells in manifestations elsewhere than in the joints of patients with HCMV-seropositive rheumatoid arthritis

Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway.

Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren\u27s syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway

What predicts negative effects of rheumatoid arthritis? A follow-up two years after diagnosis

We aimed at analyzing important predictive factors for experienced negative emotional and social effects of rheumatoid arthritis (RA) two years after diagnosis in patients aged 18–65 years. The first group included 41 participants, who had psychosocial problems (PSP) already at diagnosis, and who received an intervention by a medical social worker to improve coping capacity and social situation. The second group included 54 patients (NPSP) without such problems at diagnosis. All completed a questionnaire mapping their social situation, the Hospital Anxiety and Depression Scale (HADS), the Sense of Coherence Scale (SOC) and the General Coping Questionnaire (GCQ) at diagnosis and after 24 months. The most pronounced predictive factor for a strong impact of the disease was high scores on HADS depression scale. After 24 months, PSP participants had a more strained life situation, with higher scores on anxiety and depression and lower on SOC, in comparison with NPSP. NPSP participants improved their coping strategies regarding self-trust, cognitive revaluation, protest and intrusion, but deteriorated regarding problem focusing and social trust. PSP patients kept their initial coping strategies, except for intrusion decreasing over time, and seemed to have a more rigid coping pattern. However, the experienced negative impact of the disease increased over time in both groups despite improvement in sickness related data. Mostly influenced areas were economy, leisure time activities and social life. We conclude that psychosocial consequences of RA are more connected to emotional and social vulnerability than are RA-related clinical factors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2193-1801-3-118) contains supplementary material, which is available to authorized users

Common vaccinations among adults do not increase the risk of developing rheumatoid arthritis: results from the Swedish EIRA study

Objective To investigate the association between vaccinations in adults and the risk of developing rheumatoid arthritis (RA). Methods Data from the Swedish population-based Epidemiological Investigation of RA case-control study encompassing 1998 incident cases of RA aged 18-70 years and 2252 randomly selected controls matched for age, sex and residency were analysed. Those vaccinated within 5 years before disease onset were compared with those not vaccinated by calculating OR with 95% CI. Results Vaccinations neither increased the risk of RA overall (OR 1.0, 95% CI 0.9 to 1.1) nor the risk of two major subgroups of RA (antibodies to citrullinated peptide-positive (ACPA-positive) and ACPA-negative disease). Furthermore, vaccinations did not increase the risk of RA in smokers or carriers of HLA-DRB1 shared epitope alleles, two groups with established risk factors for RA. Conclusions In this case-control study of incident cases of newly diagnosed RA, no increased risk of RA following immunisation was observed for vaccinations overall or for any specific vaccination. This indicates that immunological provocation of adults with commonly used vaccines in their present form carries no risk of RA. These findings should be implemented among public healthcare providers in order to encourage vaccinations according to recommended national vaccination schedules

Associations between everyday physical activity and morale in older adults

Studies that objectively investigate patterns of everyday physical activity in relation to well-being and that use measures specific to older adults are scarce. This study aimed to explore objectively measured everyday physical activity and sedentary behavior in relation to a morale measure specifically constructed for older adults. A total of 77 persons (42 women, 35 men) aged 80 years or older (84.3 ± 3.8) wore an accelerometer device for at least 5 days. Morale was measured with the Philadelphia Geriatric Center Morale Scale (PGCMS). PGCMS scores were significantly positively associated with number of steps, time spent stepping, and time spent stepping at >75 steps per minute. Sedentary behavior did not associate with PGCMS. Promoting PA in the form of walking at any intensity–or even spending time in an upright position—and in any quantity may be important for morale, or vice versa, or the influence may be bidirectional

CD4CD28T cells from peripheral blood and synovial fluid show human cytomegalovirus specificity

<p><b>Copyright information:</b></p><p>Taken from "Skewed distribution of proinflammatory CD4CD28T cells in rheumatoid arthritis"</p><p>http://arthritis-research.com/content/9/5/R87</p><p>Arthritis Research & Therapy 2007;9(5):R87-R87.</p><p>Published online 7 Sep 2007</p><p>PMCID:PMC2212553.</p><p></p> The functional capacity of CD4CD28T cells in peripheral blood (PB) and synovial fluid (SF) was investigated after stimulation of mononuclear cells from paired PB and SF from rheumatoid arthritis patients by plate-bound anti-CD3 antibodies. The reactivity of CD4CD28T cells in paired PB and SF to human cytomegalovirus (HCMV) antigens was analysed after stimulation by the pp65 or immediate early (IE) antigens

Skewed distribution of CD4CD28T cells in synovial fluid and peripheral blood

<p><b>Copyright information:</b></p><p>Taken from "Skewed distribution of proinflammatory CD4CD28T cells in rheumatoid arthritis"</p><p>http://arthritis-research.com/content/9/5/R87</p><p>Arthritis Research & Therapy 2007;9(5):R87-R87.</p><p>Published online 7 Sep 2007</p><p>PMCID:PMC2212553.</p><p></p> Paired samples of synovial fluid (SF) and peripheral blood (PB) from 128 rheumatoid arthritis patients were compared for the frequency of CD4CD28T cells by flow cytometry. Frequencies of CD4CD28T cells in SF tend to be higher in patients with large populations in PB. Comparison of the frequency of CD4CD28T cells in SF from two different synovial compartments. Open circle, elbow; open squares, shoulder joints. Frequencies of CD4CD28T cells in SF and PB in patients seronegative and seropositive for human cytomegalovirus (HCMV). Frequencies of CD4CD28T cells in paired PB and SF of patients seropositive for HCMV

Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases

Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogren's syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account