Objective: Defensins are immunomodulatory peptides and components of the innate immune response. They have been shown to be modulated in various disease states and in response to inflammatory stimuli. Recently, alpha-defensins have been implicated in the pathogenesis of autoimmune diseases. In order to explore whether these defensins may have a role in the pathogenesis of systemic lupus erythematosus (SLE), we sought to determine whether altered expression can be found in SLE patients. Material and Methods: Serum and EDTA-blood of 50 SLE patients who fulfilled the American College of Rheumatology (ACR) criteria (aged 41.4 ± 13.3 years) and 28 age- and sex-matched healthy controls were collected. Real-time polymerase chain reaction with gene-specific primers for human neutrophil peptides (HNPs), human beta-defensin 2 and 3 (hBD2, 3) in isolated polymorphonuclear cells and enzyme-linked immunosorbent assay (ELISA) in serum samples were performed. Results of SLE patients were compared with the control group and correlated to routine laboratory parameters, clinical data and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results: SLE patients were predominantly female (90%) with a mean SLEDAI of 5.7 ± 6.1. In sera, patients displayed higher amounts of hBD2 and HNPs when compared with healthy controls. Furthermore, hBD2 correlated with levels of anti-dsDNA antibodies, erythrocyte count and the SLEDAI. Elevated values were observed in patients with myositis (n = 4). Serum HNPs on the other hand correlated with the neutrophil count and was elevated in patients with a rash (n = 7). Lupus patients suffering from transverse myelitis (n = 3) had raised serum-values of both HNPs and hBD2. While no mRNA of hBD2 or hBD3 was detected in polymorphonuclear cells, HNP mRNA was found in both healthy controls and patients without significant difference. Lupus nephritis and rash were associated with higher amounts of HNP mRNA, and the relative amount of copies correlated positively with the SLEDAI and negatively with C3 measurements. Conclusions: Serum levels of hBD2 and HNPs are elevated in SLE. The correlations of hBD2 and HNPs to established disease activity parameters and distinct clinical situations suggest that innate immune mechanisms are activated. Defensins may be involved in SLE pathogenesis.

Remission is arguably the ultimate therapeutic goal in rheumatoid arthritis (RA). Applying modern strategies, clinical remission can be achieved in a substantial number of patients with early RA (ERA). Even in those patients, the number and scope of erosions can increase. We, therefore, investigated the value of MRI for the detection of radiological progression in patients with DAS28 improvement and/or clinical remission of the German Remission-plus cohort. Data-sets of 80 RA patients (according to 2010 ACR/EULAR criteria) from the Remission-plus study cohort, who fulfilled the following criteria, were retrospectively analysed: availability of two consecutive MRI scans (low-field MRI, follow-up interval 1 year) of the clinically dominant hand and wrist, and the presence of DAS28 (CRP) scores at both time points, which was used to assess disease activity. Seventy-one of the 80 investigated patients presented a numerical improvement of the DAS28 (CRP) after 12 months (DAS28(CRP) T0 average (Ø) 4.96, SD 1.2; DAS28 T4 (12 month) Ø 2.6, SD 1.0), 73% of them also improved in the RAMRIS-Score, while 24% demonstrated an increase despite DAS28 improvement and 3% showed equal values. 48% of patients who improved in the DAS28 reached EULAR remission. 41% of these patients had an increase in the RAMRIS Erosion-subscore after 12 months. When considering EULAR response criteria (non-response (n = 7), moderate response (n = 19), good response (n = 45)), an increase of erosions was found in 71.4% of non-responders, 52.6% of moderate responders, and 31.1% of good responders after 12 months, all compared to baseline. Up to 40% of patients in this study demonstrated a progressive erosive disease detected by MRI despite DAS28 improvement or EULAR remission. Future studies are needed to determine the prognostic clinical impact of disease progression in MRI despite clinical remission, and to investigate if DAS28 remission may be an insufficient therapeutic goal and should be accompanied by MRI remission criteria.

Introduction: Synovial inflammation and joint destruction in rheumatoid arthritis (RA) may progress despite clinical remission. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly used to detect synovial inflammation in RA. Although small joints such as metacarpophalangeal (MCP) joints are mainly affected by RA, MRI findings have never been directly compared to histological synovitis in MCP synovial tissue. The objective of the current study was therefore to analyse if DCE-MRI relates to histological signs of synovitis small RA joints. Methods: In 9 RA patients, DCE-MRI (3 Tesla, dynamic 2D T1 weighted turbo-flash sequence) of the hand was performed prior to arthroscopically-guided synovial biopsies from the second MCP of the imaged hand. Maximum enhancement (ME), rate of early enhancement, and maximum rate of enhancement were assessed in the MCP. Synovial biopsies were stained for determination of sublining CD68 and the Synovitis Score. Correlations between MRI and histological data were calculated according to Spearman. Results: ME of the MCP significantly correlated to sublining CD68 staining (r = 0.750, P = 0.02), the Synovitis Score (r = 0.743, P = 0.02), and the subscores for lining layer hypertrophy (r = 0.789, P = 0.01) and cellular density (r = 0.842; P = 0.004). Conclusions: Perfusion imaging of synovial tissue in RA finger joints employing DCE-MRI reflects histological synovial inflammation. According to our study, ME is the most closely associated parameter amongst the measures considered.

Caseins are major constituents of mammalian milks that are thought to be exclusively expressed in mammary glands and to function primarily as a protein source, as well as to ameliorate intestinal calcium uptake. In addition, proinflammatory and immunomodulatory properties have been reported for bovine caseins. Our aim was to investigate whether human casein α s1 (CSN1S1) is expressed outside the mammary gland and possesses immunomodulatory functions in humans as well. For this purpose, CSN1S1 mRNA was detected in primary human monocytes and CD4⁺ and CD8⁺ T cells, but not in CD19⁺ B cells. CSN1S1 protein was traceable in supernatants of cultured primary human CD14⁺ monocytes by ELISA. Similarly, CSN1S1 mRNA and protein were detected in the human monocytic cell lines HL60, U937, and THP1 but not in Mono Mac 6 cells. Moreover, permeabilized human monocytes and HL60 cells could be stained by immunofluorescence, indicating intracellular expression. Recombinant human CSN1S1 was bound to the surface of Mono Mac 6 cells and upregulated the expression of GM-CSF mRNA in primary human monocytes and Mono Mac 6 cells in a time- and concentration-dependent manner. A similar increase in GM-CSF protein was found in the culture supernatants. CSN1S1-dependent upregulation of GM-CSF was specifically blocked by the addition of the p38 MAPK inhibitor ML3403. Our results indicated that human CSN1S1 may possess an immunomodulatory role beyond its nutritional function in milk. It is expressed in human monocytes and stimulates the expression of the proinflammatory cytokine GM-CSF.

Synovial biopsies, gained either by blind needle biopsy or minimally invasive arthroscopy, offer additional information in certain clinical situations where routine assessment has not permitted a certain diagnosis. In research settings, synovial histology and modern applications of molecular biology increase our insight into pathogenesis and enable responses to treatment with new therapeutic agents to be assessed directly at the pathophysiological level. This review focuses on the diagnostic usefulness of synovial biopsies in the light of actual developments.

Objective: To comprehensively assess associations of site-specific CD4 ⁺ -T-cell hypomethylation of the CD40-Ligand gene ( CD40L ) with disease activity of women with systemic lupus erythematosus (SLE). Methods: CpG-sites within the DNA of the promotor and two enhancer regions (n = 22) of CD40L were identified and numbered consecutively. The rate of methylated DNA in isolated CD4 ⁺ -T-cells of women with SLE were quantified for each methylation site by MALDI-TOF. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Associations of site-specific methylation rates with the SLEDAI scores were assessed by linear regression modelling. P values were adjusted according to Bonferroni-Holm as indicated. Results: 60 female SLE patients participated in the study (age 45.7 ± 11.1 years, disease duration 17.0 ± 8.3 years). Significant associations to the SLEDAI were noted for CpG22 hypomethylation of the promotor (β = −40.1, p = 0.017, adjusted p = 0.027), trends were noted for CpG17 hypomethylation of the promotor (β = −30.5, p = 0.032, adjusted p = 0.6), and for CpG11 hypermethylation of the second enhancer (β = 15.0, p = 0.046, adjusted p = 0.8). Conclusion: Site-specific hypomethylation of the CD40L promotor in CD4 ⁺ -T-cells show associations with disease activity in female SLE patients.