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Tumor necrosis factor (TNF) plays an essential role in the immunologic maintenance of Mycobacterium tuberculosis infection. Although an increased rate of tuberculosis has been reported in humans treated with anti-TNF biological agents, disparate rates of disease have been observed between those treated with infliximab, an anti-TNF antibody, and etanercept, a TNF-neutralizing TNF receptor (TNFR) fusion molecule. We compared the effects of anti-TNF antibody and soluble TNFR fusion molecule in the murine model of tuberculosis. Systemic TNF neutralization was equivalent between these molecules, and both resulted in rapid morbidity at the initiation of infection. During chronic infection, administration of the receptor fusion molecule allowed the control of infection, whereas antibody treatment caused mice to die within a month. We provide evidence of decreased penetration into the granulomas by the receptor fusion molecule, compared with antibody. These findings begin to clarify the mechanistic difference between anti-TNF agents and their role in the exacerbation of tuberculosis.

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ObjectiveTo our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA.MethodsWe conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real-time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence.ResultsGlobally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin-17 (IL-17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon-γ gene signatures in both tissues. These results were confirmed with real-time PCR.ConclusionThis is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL-17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA.

Tumor necrosis factor (TNF) antagonists are efficacious in the treatment of various autoimmune diseases. Two classes of TNF antagonists are currently commercially available: soluble TNF receptor-Fc fusion proteins (etanercept) and anti-TNF mAbs (adalimumab and infliximab). The classes differ in molecular structures and mechanisms of action. The interactions between TNF antagonists with TNF molecules were characterized. The anti-TNF mAbs, but not the soluble TNF receptor, formed visible lines of precipitation in Ouchterlony assays. The molecular weights of complexes formed by TNF (52 kDa) with either etanercept (130 kDa), adalimumab (150 kDa), or infliximab (average 165 kDa) were determined by size exclusion chromatography-light-scattering assays. Etanercept and TNF formed complexes of 180 and 300 kDa, representing one and two etanercept monomers bound to a TNF trimer, respectively. Adalimumab and infliximab formed a variety of complexes with TNF with molecular weights as high as 4,000 and 14,000 kDa, respectively, suggesting the presence of complexes with a wide range of sizes and stoichiometries. The absence of large complex formation with the binding of soluble receptor-fusion proteins to TNF may account for the different clinical efficacy and safety profiles of the two classes of TNF antagonists.

After immunization with A/New Jersey/76 and A/Victoria/75 influenza vaccines, 11 patients with systemic lupud erythematosus were serially evaluated for changes in disease activity, serologic abnormalities, and their capability to generate specific antibodies. One patient, with active disease, developed a diffuse, proliferative glomerulonephritis. None of the other patients or control subjects had significant local or systemic side effects. Significant levels of antibodies were generated to A/New Jersey/76 in eight of the 11 patients and in seven of eight control subjects and to A/Victoria/75 in seven of 11 patients and five of eight control subjects. The geometric mean responses of both total and IgG antibodies to each viral antigen were no different in patients with systemic lupus erythematosus than in control subjects. In patients with stable systemic lupus erythematosus, immunization with killed influenza viral vaccine appears to be safe and effective.

contention includes: the presence of circulating DNA (l), antibodies to DNA (2), immune complexes composed of DNA and anti-DNA antibody (3), activation of the complement cascade leading to hypocomplementemia, and deposition of DNA, anti-DNA antibody, and complement components in tissues, particularly in glomeruli (4). The emergence of immunologic methods for measuring complement components (6) and antibodies to DNA (7,8) provided a rich source of serologic data in patients with SLE. However, the correlation of results from these tests with clinical data has proved disappointing.Application of recently developed sensitive and specific methods for detecting circulating immune complexes (CIC) has documented an increased prevalence of immune complexes in SLE (9-13). These assays for CIC may have value in the assessment of clinical activity of disease. Tron and Bach (14) have demonstrated that patients with more severe manifestations of SLE tend to have higher levels of CIC, but to date, determinations of CIC have not been specifically correlated with clinical assessment, thus none have proved to be of consistent value in predicting change in disease activity in SLE.The present study was undertaken to prospectively evaluate the potential value of serial measurements of CIC in patients with SLE, unselected for particular organ system involvement. A panel of serologic tests including C3, anti-DNA antibody, and two methods for detecting CIC were performed and correlated with the presence of, as well as changes in, disease activity. The results indicate that the solid phase Clq binding assay for circulating immune complexes correlates best with the presence of clinical manifestations and changes in activity of SLE.

Objective. To analyze clinical fluids for the presence of Borreliu butgdo#eri DNA using the polymerase chain reaction (PCR).Methods. We utilized a modified, nested PCR to detect the presence of Borreliu DNA in 99 samples of serum, urine, cerebrospinal fluid (CSF), or synovial fluid obtained from 44 patients with various stages of Lyme disease and 47 control subjects. Primer specificity was corroborated by examining 2 DNA data banks, testing against DNA from other organisms, and confirming results with a second set of nested primers.Results. Nested PCR was capable of detecting DNA from fewer than 10 organisms in 1 ml of fluid. The specificity of this technique was 96.4%, with a sensitivity of 76.7%. Although the specificity was uniformly high, the sensitivity was dependent upon the body fluid being tested: CSF loo%, urine loo%, synovial fluid 80%, and serum 59%. The rate of false-positive results was 3.6%.