Pathogenic anti-DNA antibodies in SLE: idiotypic families and genetic origins

We have adopted an idiotypic approach to study the double stranded DNA (dsDNA) binding antibodies of systemic lupus erythematosus (SLE). Three anti-idiotypic reagents, 8.12, 3I, and F4, identify cross reactive idiotypes that are each expressed on anti-dsDNA antibodies in the sera of many patients with SLE. These idiotypic antibodies are implicated in the pathogenesis of SLE as they are present in immune complex deposits in the kidneys of patients with SLE glomerulonephritis. The autoantibody associated idiotypes are also expressed on antibodies that do not bind DNA. We are investigating the origin of the pathogenic anti-dsDNA antibodies of SLE by comparing the autoantibodies, the antibodies to foreign antigens, and the myeloma proteins that express each SLE associated idiotype. In conjunction with serological analysis of these idiotypic systems, molecular genetic studies indicate that both the 8.12 and the 3I autoantibody associated idiotypes may be germline encoded, while the F4 idiotype is generated by somatic mutation. The data further suggest that the antigenic specificity of the pathogenic anti-DNA antibodies of SLE is acquired through somatic mutation of germline immunoglobulin genes. By studying the regulation of genes capable of encoding pathogenic autoantibodies, in both SLE patients and non-autoimmune individuals, we may be able to elucidate the pathogenesis of autoimmune disease and begin to design more effective therapeutic interventions.     

Molybdenum(0) tricarbonyl and tetracarbonyl complexes with a cationic pyrazolylpyridine ligand: synthesis,crystal structures and catalytic performance in olefin epoxidation

The synthesis of molybdenum(0) tricarbonyl and tetracarbonyl complexes of the form [Mo(CO)₃(ptapzpy)Br] (1) and cis-[Mo(CO)₄(ptapzpy)]Br (2) is reported, where ptapzpy = 2-(1-propyltrimethylammonium-3-pyrazolyl)pyridine. Preparation of these derivatives was accomplished either through thermal replacement of CO in Mo(CO)₆ (for 1) or substitution under milder conditions of piperidine ligands in the precursor cis-[Mo(CO)₄(pip)₂] (for 2). The crystal structures of the ligand [ptapzpy]Br and complexes 1 and 2 were determined. Thermal treatment of 2 at 125–150 °C leads to mono decarbonylation and formation of 1. On the other hand, oxidative decarbonylation of 1 and 2 by reaction with tert-butylhydroperoxide (TBHP, 10 equiv.) gives a molybdenum oxide hybrid material formulated as [Mo₃O₉([ptapzpy]Br)₂]·nH₂O (3), which was characterised by FT-IR and Raman spectroscopy, thermogravimetric analysis, and ¹³C{¹H} CP MAS NMR spectroscopy. Compounds 1–3 were effective (pre)catalysts for the epoxidation of cis-cyclooctene at 55 °C with aqueous H₂O₂ or TBHP (slightly better results were obtained with the former). The characterisation of the Mo-containing solids isolated after the catalytic reaction showed that poorly soluble β-octamolybdate salts, (L)_x[Mo₈O₂₆], were formed from 1–3 with TBHP and from 1 with H₂O₂, while soluble oxoperoxo species were formed from 3 with H₂O₂. These findings helped to explain the different catalytic performances obtained.

The oxidative decarbonylation and catalytic chemistry of molybdenum(0) tricarbonyl and tetracarbonyl complexes containing the same diimine ligand are compared.     

Coincident Kikuchi-Fujimoto’s disease and adult-onset Still’s disease: report of a patient from an uncommonly affected population and case-directed systematic review

Clinical Rheumatology - Kikuchi-Fujimoto's disease (KFD) and adult-onset Still’s disease (AOSD) are rare idiopathic inflammatory conditions of unknown etiology. Ten prior instances of KFD...     

The neutrophil: function and regulation in innate and humoral immunity

The neutrophil is a critical effector cell in humoral and innate immunity and plays vital roles in phagocytosis and bacterial killing. Discussed here are the neutrophil components necessary for these processes and the diseases in which these components are either lacking or dysfunctional, illustrating that normal neutrophil function is vital for health.     

Nitric oxide synthases and osteoarthritis

The production of nitric oxide (NO) by chondrocytes is increased in human osteoarthritis. The excessive production of NO inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, NO promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. Thus, NO produced by activated chondrocytes in diseased cartilage may modulate disease progression in osteoarthritis and should therefore be considered a potential target for therapeutic intervention.     

Update on gout: Pathophysiology and potential treatments

After several decades of senescence, the twin fields of hyperuricemia and gout have again regained attention in both the scientific and clinical spheres, and this review highlights several recent advancements. Specifically, we review newly discovered mechanisms of uric acid-induced inflammation, uric acid’s putative role as a “danger signal” in innate immunity, the possible link between hyperuricemia and cardiovascular disease, and evolutionary evidence suggesting that hyperuricemia conferred a survival advantage in primates (when the gene for uricase was lost) several million years ago. Finally, we provide an overview of the current approach to gout, as well as what treatments are on the horizon.     

Update on fibromyalgia therapy

Primary fibromyalgia, a poorly-understood chronic pain syndrome, is characterized by widespread musculoskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specific regions of localized tenderness, all in the absence of otherwise apparent organic disease. While the etiology of fibromyalgia is unclear, accumulating data suggest that disordered central pain processing likely plays a role in the pathogenesis of symptoms. Although various pharmacological treatments have been studied and espoused for treating fibromyalgia, no single drug or group of drugs has proved to be particularly useful in treating fibromyalgia patients as a whole, and only one drug to date has earned U.S. Food and Drug Administration approval for treating the syndrome in the United States. This review critically and systematically evaluates clinical investigations of medicinal and nonmedicinal treatments for fibromyalgia dating from 1970 to 2007.