IntroductionBoth clinical experience and experimental evidence have suggested that Adrenocorticotropic hormone (ACTH) might directly exert immunomodulatory effects not dependent on adrenal steroidogenesis.MethodsThe direct effects of H.P. Acthar Gel® (Acthar), a repository preparation containing a porcine ACTH analogue, on human B lymphocyte function were studied in vitro using peripheral blood B cells isolated using anti-CD19 coated magnetic beads and activated by interleukin 4 (IL-4) and CD40 ligand (CD40L). Analysis of expression of messenger RNA (mRNA) encoding activation-induced cytidine deaminase (AICDA) was carried out by quantitative real-time polymerase chain reaction (PCR). Cellular proliferation was assessed by a flow cytometric technique using intracellular staining with carboxyfluorescein succinimidyl ester (CFSE). Immunoglobulin G (IgG) production was measured in cell supernatants using an immunoassay.ResultsActhar was found to exert acute, dose-dependent inhibitory effects on IL-4/CD40L–mediated induction of the expression of activation-induced cytidine deaminase (AICDA) after 24 hours, as well as sustained inhibition of B cell proliferation and IgG production during five more days of culture, without deleterious effects on B cell viability.ConclusionsThese experiments demonstrate that Acthar can exert direct effects on the humoral immune system independent of any role in the regulation of adrenal steroidogenesis. Although the impact of these findings on clinical disease was not evaluated in this study, these data support the therapeutic potential of Acthar for the management of autoimmune diseases characterized by B cell activation and aberrant humoral immune function.

Objective. The study goals were to evaluate performance of SLE classification criteria, to define patients with incomplete lupus erythematosus (ILE), and to probe for features in these patients that might be useful as indicators of disease status and hydroxychloroquine response. Methods. Patients with ILE (N = 70) and SLE (N = 32) defined by the 1997 American College of Rheumatology criteria were reclassified using the 2012 Systemic Lupus International Collaborating Clinics criteria. Disease activity, patient reported outcomes, and levels of Type I interferon- (IFN-) inducible genes, autoantibodies, and cytokines were measured. Subgroups treated with hydroxychloroquine (HCQ) were compared to patients not on this drug. Results. The classification sets were correlated (R2 = 0.87). ILE patients were older (P = 0.0043) with lower disease activity scores (P < 0.001) and greater dissatisfaction with health status (P = 0.034) than SLE patients. ILE was associated with lower levels of macrophage-derived cytokines and levels of expressed Type I IFN-inducible genes. Treatment of ILE with HCQ was associated with better self-reported health status scores and lower expression levels of Type I IFN-inducible genes than ILE patients not on HCQ. Conclusion. The 2012 SLICC SLE classification criteria will be useful to define ILE in trials. Patients with ILE have better health status and immune profiles when treated with HCQ.

Repository corticotrophin injection (RCI, H.P Acthar gel) has been approved for use in the management of multiple autoimmune and inflammatory diseases for more than a half-century, but its mechanism of action is not well understood. We used RNA-Seq methods to define RCI-regulated mRNAs in cultured human B cells under conditions of activation by interleukin (IL)-4 and CD40 ligand. Following IL-4/CD40L activation and RCI treatment we found up-regulation of 115 unique mRNA transcripts and down-regulation of 80 unique mRNAs. The effect on these RNA levels was dose-dependent for RCI and was distinct from changes in mRNA expression induced by treatment with a potent synthetic glucocorticoid. RCI down-regulated mRNAs were observed to include a significant over-representation of genes critical for B cell proliferation under activating conditions. These data confirm that RCI exerts direct effects on human B cells to modulate mRNA expression in specific pathways of importance to B cell function and that, at the molecular level, the effects of RCI are distinct from those exerted by glucocorticoids.

No abstract

Results Tregs from SLE patients showed a significantly reduced number,elevated apoptosis rates and impared suppressive capacity compared with NCs.The increased Tregs apoptosis was negatively correlated with the total number of Tregs and positively correlated with disease activities.Microarray profiles of Tregs from SLE subjects reveal a cellular response that could make the cells sensitive to apoptosis,partially due to the stress responses,DNA-damaging and cytokine stimulation. Conclusions This global picture of pathway-specific expression signatures is a step further dissecting Treg cells defects in the pathogenesis of SLE,and may shed light on the newly therapeutic strategies towards the aberrant Tregs apoptosis and reconstruction of SLE immune homeostasis.

Effects of melanocortin peptides on human B cells were described more than two decades ago, but therapeutic applications have not been fully explored. This study examined B cell responses to a clinically available melanocortin peptide preparation, repository corticotropin gel. Peripheral blood B cells isolated from healthy donors using CD19 magnetic beads were cultured with and without Interleukin 4 (IL-4) and CD40 ligand (CD40L). Repository corticotropin or Placebo Gels were added in serial dilutions. Cultures were harvested after 7 days for measurement of secreted IgG by ELISA, B cell proliferation using CFSE and viability with trypan blue. Mean IgG in IL-4/CD40L-stimulated cultures was 241.4 ng/ml and was reduced in a dose-dependent fashion with corticotropin gel; maximal suppression was to 65.55 ng/ml (p= 0.008; n=8). Addition of Placebo Gel or dexamethasone (1μM) to IL-4/CD40L cultures resulted in no change in IgG (240.3 and 248.1 ng/ml). The effect on IgG was paralleled by inhibition of B cell proliferation. In IL4/CD40L-stimulated cultures, 61% of cells were dividing, vs 8% with corticotropin gel (p&lt;0.0001) and 58% with Placebo Gel (ns). Inhibition of proliferation was not accompanied by increased cell death. Repository corticotropin gel exerted dose-dependent inhibition of IgG production and B cell proliferation without effects on cell viability. These data support potential efficacy of repository corticotropin gel in diseases characterized by B cell activation.

No abstract

analyses, adjustment had minimal effect on results, indicating that the effect of confounding variables was minimal. Conclusions The present study improves the certainty that poverty is etiologically related to damage and not an artefact of study design.