Translational research : the journal of laboratory and clinical medicine
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The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial, and the interferon regulatory factors (IRFs) play an important role. Autoantibodies formed in SLE target nuclear antigens, and immune complexes formed by these antibodies contain nucleic acid. ⋯ Recent studies suggest that these genetic variations contribute to the break in humoral tolerance that allows for nucleic acid binding autoantibodies, and that the same polymorphisms also augment IFN-I production in the presence of these autoantibody immune complexes, forming a feed-forward loop. In this review, we will outline major features of the PRR/IRF systems and describe the role of the IRFs in human SLE pathogenesis.
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The complement inhibitor eculizumab is a humanized monoclonal antibody against C5. It was developed to specifically target cleavage of C5 thus preventing release of C5a and activation of the terminal pathway. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are 2 diseases with distinctly different underlying molecular mechanisms. ⋯ Critical to the development of either disease is activation of the terminal complement pathway. Understanding this step has led to the study of eculizumab as a treatment for these diseases. In clinical trials, eculizumab is proven to be effective and safe in PNH and aHUS.
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Tumor necrosis factor (TNF) production is amplified in several autoimmune disorders. In the 1990s, it became a validated therapeutic target used for the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease. Biologic drugs targeting TNF include engineered monoclonal antibodies and fusion proteins. ⋯ Pharmacokinetics of the TNF inhibitors is affected by routes of administration, clearance mechanisms of immunoglobulins, and immunogenicity. Finally, strategies for management of treatment efficacy and increasing evidence for monitoring of serum concentration of TNF inhibitors are discussed, assessing for the presence of the antidrug antibodies and the different analytical methods available for laboratory testing. As clinical applications of the TNF inhibitors expand, and other classes join the revolution in the treatment of chronic inflammatory disorders, therapeutic drug monitoring of biologics will become increasingly important, with the potential to dramatically improve patient care and management.