Manipulation of B-cell responses with histone deacetylase inhibitors.

Histone deacetylase inhibitors (HDACi) are approved for treating certain haematological malignancies, however, recent evidence also illustrates they are modulators of the immune system. In experimental models, HDACi are particularly potent against malignancies originating from the B-lymphocyte lineage. Here we examine the ability of this class of compounds to modify both protective and autoimmune antibody responses. In vitro, HDACi affect B-cell proliferation, survival and differentiation in an HDAC-class-dependent manner. Strikingly, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduces autoreactive plasma-cell numbers, autoantibodies and nephritis, while other immune parameters remain largely unaffected. Immunized control mice treated with panobinostat or the clinically approved HDACi vorinostat have significantly impaired primary antibody responses, but these treatments surprisingly spare circulating memory B cells. These studies indicate that panobinostat is a potential therapy for B-cell-driven autoimmune conditions and HDACi do not induce major long-term detrimental effects on B-cell memory.

Vitamin D and systemic lupus erythematosus: continued evolution.

Vitamin D is a steroid hormone that has well-established roles in calcium and bone metabolism. Vitamin D has more recently become recognized for its role in the immune response and its potential immunomodulatory effects in autoimmune diseases, including systemic lupus erythematosus (SLE). This review provides a summary of the recent literature regarding vitamin D and SLE, as well as current recommendations for vitamin D supplementation in patients with SLE.

Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis.

Arthrogenic alphaviruses, such as Ross River virus (RRV), chikungunya, Sindbis, mayaro and o'nyong-nyong viruses circulate endemically worldwide, frequently causing outbreaks of polyarthritis. The exact mechanisms of how alphaviruses induce polyarthritis remain ill defined, although macrophages are known to play a key role. Macrophage migration inhibitory factor (MIF) is an important cytokine involved in rheumatoid arthritis pathogenesis. Here, we characterize the role of MIF in alphavirus-induced arthritides using a mouse model of RRV-induced arthritis, which has many characteristics of RRV disease in humans. RRV-infected WT mice developed severe disease associated with up-regulated MIF expression in serum and tissues, which corresponded to severe inflammation and tissue damage. MIF-deficient (MIF(-/-)) mice developed mild disease accompanied by a reduction in inflammatory infiltrates and muscle destruction in the tissues, despite having viral titers similar to WT mice. In addition, reconstitution of MIF into MIF(-/-) mice exacerbated RRV disease and treatment of mice with MIF antagonist ameliorated disease in WT mice. Collectively, these findings suggest that MIF plays a critical role in determining the clinical severity of alphavirus-induced musculoskeletal disease and may provide a target for the development of antiviral pharmaceuticals. The prospect being that early treatment with MIF-blocking pharmaceuticals may curtail the debilitating arthritis associated with alphaviral infections.

Effects of glucocorticoids on inflammation and arthritis.

PURPOSE OF REVIEW: Glucocorticoids are used in the treatment of most rheumatic diseases, and are used chronically in up to 50% of cases of rheumatoid arthritis. The frequency of their use has in the past been incompletely supported by trial evidence of their benefit and by incomplete understanding of their mechanisms of action. The present review will examine significant recent publications relating to glucocorticoids of relevance to rheumatology RECENT FINDINGS: The basic science of glucocorticoid action has advanced considerably in the review period. Major advances include demonstration of the function of glucocorticoid-induced anti-inflammatory proteins such as mitogen-activated protein kinase phosphatase-1, expanded understanding of alternately spliced isoforms of the glucocorticoid receptor, and major steps in understanding factors regulating glucocorticoid sensitivity in disease. Clinical studies have also had major developments, most strikingly with the publication of two randomized prospective studies on the efficacy of glucocorticoids in preventing erosions in rheumatoid arthritis. SUMMARY: Despite over 50 years of glucocorticoid use in rheumatology, basic science and clinical studies continue to yield intriguing new data. The quest for therapeutic agents with the beneficial effects of glucocorticoids but lacking their harmful effects is aided by this progress.