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Objective In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fcγ receptor–mediated uptake of nucleic acid–containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo. Methods Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects. Results Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (μMT), C3−/−, and CD18−/− mice. Intravenous infusion of normal IgM, but not IgG, restored the IFN signature in μMT mice, and the IFN signature in wild-type mice was inhibited by depleting complement, suggesting that opsonization by IgM and complement is involved in IFN production. Consistent with that possibility, the levels of “natural” IgM antibodies reactive with dead cells were increased in pristane-treated wild-type mice compared with untreated controls, and in vivo phagocytosis of dead cells was impaired in C3-deficient mice. To examine the clinical relevance of these findings, we identified 10 C4-deficient patients with lupus-like disease and compared them with 152 C4-intact patients and 21 healthy controls. In comparison with C4-intact patients, C4-deficient patients had a different clinical/serologic phenotype and lacked the IFN signature. Conclusion These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.

Purpose: The purpose of this pilot clinical study is to assess three-dimensional (3-D) quantitative photoacoustic tomography (qPAT) for in vivo detection of osteoarthritis (OA) in the finger joints.Methods: All subject data were handled in compliance with the rules and regulations concerning the privacy and security of protected health information under HIPAA. Seven female subjects (two OA patients and five healthy controls) entered the study and their distal interphalangeal (DIP) joints were examined by a 3-D photoacoustic scanner. 3-D optical absorption coefficient images of all the photoacoustically examined joints were recovered using a 3-D qPAT reconstruction algorithm.Results: The recovered quantitative photoacousticimages revealed obvious difference in the optical absorption coefficient of the joint cavity (cartilage and synovial fluid) between the OA and healthy joints. Quantitative analysis of the joints also indicated an apparent difference in the recovered joint spacing between the OA and healthy subjects.Conclusion: This initial clinical evaluation suggests that it is feasible to detect osteoarthritis in the finger joints with our 3-D qPAT approach, which has paved the way to further statistically evaluate the diagnostic performance of the 3-D qPAT approach in comparison with radiography or magnetic resonance imaging (MRI) on a sample of hand osteoarthritis.

Purpose: The aim of this study was to investigate the potential use of multimodality functional imaging techniques to identify the quantitative optical findings that can be used to distinguish between osteoarthritic and normal finger joints. Methods: Between 2006 and 2009, the distal interphalangeal finger joints from 40 female subjects including 22 patients and 18 healthy controls were examined clinically and scanned by a hybrid imaging system. This system integrated x-ray tomosynthetic setup with a diffuse optical imaging system. Optical absorption and scattering images were recovered based on a regularization-based hybrid reconstruction algorithm. A receiver operating characteristic curve was used to calculate the statistical significance of specific optical features obtained from osteoarthritic and healthy joints groups. Results: The three-dimensional optical and x-ray images captured made it possible to quantify optical properties and joint space width of finger joints. Based on the recovered optical absorption and scattering parameters, the authors observed statistically significant differences between healthy and osteoarthritis finger joints. Conclusions: The statistical results revealed that sensitivity and specificity values up to 92% and 100%, respectively, can be achieved when optical properties of joint tissues were used as classifiers. This suggests that these optical imaging parameters are possible indicators for diagnosing osteoarthritis and monitoring its progression.

Anti–cyclic citrullinated peptide (anti-CCP) using a peptide of filaggrin has been used extensively as a new serologic marker of rheumatoid arthritis (RA) (1,2). Many studies have confirmed that anti-CCP enzyme-linked immunosorbent assay (ELISA) is as sensitive as rheumatoid factor (RF) and much more specific for RA among various rheumatic diseases (2). However, anti-CCP in other diseases has been less well studied. Patients with certain infectious diseases, such as hepatitis C and tuberculosis (TB), can present with arthritis and frequently also have serum RF, making it difficult to distinguish infectious disease–related arthritis from RA. Thus, the utility of anti-CCP testing under these clinical circumstances is important. Studies in patients with hepatitis C viral infection showed the absence of anti-CCP, in contrast to frequent RF positivity (3). However, a recent study showed the presence of anti-CCP in 32% of patients with active pulmonary TB (4). Patients with TB can exhibit various forms of arthropathy, including tuberculous arthritis and reactive arthritis (5). Some of these patients’ diseases may mimic early RA and may be difficult to diagnose. Thus, anti-CCP–positive test results in these patients can be misleading. Early studies showed that anti-CCP antibodies in RA patients are specific for citrullinated peptide and do not react with unmodified peptide (1). However, the majority of clinical studies on anti-CCP are based on commercial anti-CCP ELISA kits and do not use an unmodified peptide as a negative control (2). In the present study, the specificity of anti-CCP–positive sera for CCP versus unmodified arginine-containing peptide (CAP) was examined in patients with TB and compared with that in patients with RA.

Objective To investigate the clinical and immunologic significance of autoantibodies to RNA helicase A (RHA) in patients with systemic rheumatic diseases. Methods The study group comprised 1,119 individuals enrolled in the University of Florida Center for Autoimmune Diseases registry from 2000 to 2005. Diagnoses were based on standard criteria. Autoantibodies were analyzed by immunoprecipitation and Western blot assays. Results Anti-RHA was observed in 17 (6.2%) of 276 patients with systemic lupus erythematosus (SLE), 2 patients with antiphospholipid antibodies, and 3 other patients, but anti-RHA was not observed in any patient with polymyositis/dermatomyositis, systemic sclerosis, rheumatoid arthritis, or Sjogren's syndrome. Anti-RHA was present in only 2.9% of African American patients, compared with 6.0% of white patients and 12–25% of patients of other races; this was in striking contrast to the frequency of anti-Sm in African American patients (27.2%). Among patients with SLE, anti-RHA was common in young patients (26% of those whose initial visit was at an age younger than 20 years versus 3–4% of those who were initially seen at ages 20–49 years) and at an early stage of disease (23% of those whose first clinic visit was within 1 year of disease onset versus 2–8% of those whose first visit was at least 1 year after disease onset). In 9 of 11 patients, levels of anti-RHA decreased to

Objective Systemic lupus erythematosus (SLE) is diagnosed according to a spectrum of clinical manifestations and autoantibodies associated with abnormal expression of type I interferon (IFN-I)–stimulated genes (ISGs). The role of IFN-I in the pathogenesis of SLE remains uncertain, partly due to the lack of suitable animal models. The objective of this study was to examine the role of IFN-I signaling in the pathogenesis of murine lupus induced by 2,6,10,14-tetramethylpentadecane (TMPD). Methods IFN-I receptor–deficient (IFNAR−/−) 129Sv mice and wild-type (WT) 129Sv control mice were treated intraperitoneally with TMPD. The expression of ISGs was measured by real-time polymerase chain reaction. Autoantibody production was evaluated by immunofluorescence and enzyme-linked immunosorbent assay. Proteinuria and renal glomerular cellularity were measured and renal immune complexes were examined by immunofluorescence. Results Increased ISG expression was observed in the peripheral blood of TMPD-treated WT mice, but not in the peripheral blood of TMPD-treated IFNAR−/− mice. TMPD did not induce lupus-specific autoantibodies (anti-RNP, anti-Sm, anti–double-stranded DNA) in IFNAR−/− mice, whereas 129Sv controls developed these specificities. Although glomerular immune complexes were present in IFNAR−/− mice, proteinuria and glomerular hypercellularity did not develop, whereas these features of glomerulonephritis were found in the TMPD-treated WT controls. The clinical and serologic manifestations observed in TMPD-treated mice were strongly dependent on IFNAR signaling, which is consistent with the association of increased expression of ISGs with lupus-specific autoantibodies and nephritis in humans. Conclusion Similar to its proposed role in human SLE, signaling via the IFNAR is central to the pathogenesis of autoantibodies and glomerulonephritis in TMPD-induced lupus. This lupus model is the first animal model shown to recapitulate the “interferon signature” in peripheral blood.

Objective Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFNα treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. Methods Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFNα4, IFNβ, the type I IFN–inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor α were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. Results Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti–Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFNα/β (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. Conclusion Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNα/β and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.