Lupus Nephritis (LN) is the leading cause of morbidity and mortality from Systemic Lupus Erythematosus (SLE) and enhanced activation of the transcription regulator nuclear factor kappa B (NF-κB) is implicated as a central player in the development and progression of LN. SLE and LN are proposed to develop through a "two-hit" process of genetic mutation or variants providing susceptibility to disease provoking molecular events in response to environmental triggers (viral infection, medication, etc.). Many of the susceptibility genes identified in association with LN are involved in NF-κB regulation and loss of function of some of the protein products in animal's results in protection from or development of SLE and LN phenotypes. This short commentary will discuss these factors and implications in precision treatment of LN.
Lupus is experienced as an “aggressive and expansive” disease affecting patients’ activities of daily living, sense of self, and social functioning [1]. Currently there is no cure. Despite substantial efforts, the lupus drug development field has witnessed only one FDA-approved therapy in the last 50 years. There is an urgent need to better our understanding of the pathogenic mechanisms for lupus, and to develop novel therapeutic strategies for both cutaneous and systemic lupus erythematosus.
OBJECTIVE:Annual influenza and pneumococcal vaccination rates remain suboptimal in patients with systemic lupus erythematosus despite their higher risk of infections and related complications. The CDC identified lack of knowledge about vaccine guidelines among adult patients and their providers as the most substantial barrier to vaccination coverage. As specialists working with particularly affected populations, rheumatologists, allergists, and immunologists can advise patients regarding gaps in recommended vaccinations.The aim of this study was to describe prescribers' perceptions of an educational activity that was developed to increase rates of appropriate pneumococcal and influenza vaccination in adults with chronic inflammatory conditions. We were interested in the impact of the educational activity on the knowledge and practice of providers.METHODS:We evaluated a multimodal educational activity aimed at increasing vaccination rates in high-risk adults. We assessed provider knowledge, perceptions of the activity, and impact on their practice. The activity was conducted at a single site "in house" education event in the live format and was disseminated nationally in print and online format.RESULTS:In the "in house" interactive education session, mean scores on the pre- and post-tests were 75% (SD 11.6%, 95% CI 70-80%) and 89% (SD 11.1%, 95% CI 85-95%; p=.0001 vs. pre-test score), respectively, demonstrating that knowledge was significantly increased after completing the activity. In the nationally available activity 93% (n=240) of respondents indicated that the activity significantly increased their awareness about the importance of vaccinations in these high-risk patients and recognition of when these vaccines were indicated or contraindicated, while 55% (n=142) planned to consequently change their practice.CONCLUSION:Provider education is a valuable strategy for practice-based improvements in vaccination coverage since provider failure to recommend vaccinations is a primary barrier in high-risk patients. Most patients received vaccinations based on physician recommendations and vaccination rates were markedly higher among patients receiving vaccine information from their providers. This educational activity increased clinicians' knowledge of and confidence in vaccinations for adults with chronic inflammatory conditions.
OBJECTIVES:Lupus flares are triggered by environmental agents that cause oxidative stress, but the mechanisms involved are unclear. The flares are characterized by oxidative modifications of proteins by 4-hydroxynonenals, malondialdehydes, carbonyls and nitration. These modifications have been proposed to induce and perpetuate lupus flares by "altered self" mechanisms. An epigenetically altered CD4+CD28+ T cell subset, caused at least in part by nitration of T cell signaling molecules, is found in patients with active lupus, and nitrated T cells are sufficient to cause lupus-like autoimmunity in animal models. The relation of protein 4-hydroxynonenals, malondialdehydes, carbonyls and nitration to lupus flares though, is unknown. We tested if the size of the epigenetically altered subset is related to disease activity and one or more of these oxidative modifications in lupus patients. We also tested the relationship between subset size, disease activity and the same oxidative modifications in Sjogren's syndrome, another autoimmune disease also associated with oxidative stress and characterized by anti-nuclear antibodies and the presence of the subset.METHODS:Lupus flare severity was quantitated using the Systemic Lupus Erythematosus Disease Activity Index, and Sjogren's flare severity using the European Sjogren's Syndrome Disease Activity Index. Subset size was determined by flow cytometry. Protein modifications were determined by ELISA.RESULTS:Only protein nitration correlated with the size of the subset in lupus and Sjogren's syndrome.CONCLUSIONS:These results support a role for protein nitration in subset size and lupus flare severity. Protein nitration may also contribute to autoantibody formation in Sjogren's syndrome.
OBJECTIVE:Lupus develops when genetically predisposed people encounter certain drugs or environmental agents causing oxidative stress such as infections and sun exposure, and then typically follows a chronic relapsing course with flares triggered by the exogenous stressors. Current evidence indicates that these environmental agents can trigger lupus flares by inhibiting the replication of DNA methylation patterns during mitosis in CD4+ T cells, altering the expression of genes suppressed by this mechanism that convert normal "helper" cells into auto reactive cells which promote lupus flares. How environmental stressors inhibit T cell DNA methylation though is incompletely understood. Protein phosphatase 5 (PP5) is a stress induced inhibitor of T cell ERK and JNK signaling in "senescent" CD4+CD28- T cells, also characterized by DNA demethylation and altered expression of genes that promote atherosclerosis. We tested if PP5 is increased in CD4+CD28+ T cells by oxidative stress, if PP5 transfection causes overexpression of methylation sensitive genes in T cells, and if PP5 is overexpressed in lupus T cells.RESULTS:PP5 was found to be overexpressed in CD4+CD28+ T cells treated with H2O2 and ONOO- and in T cells from lupus patients.CONCLUSION:The results indicate that PP5 increases expression of methylation sensitive T cell genes, and may contribute to the aberrant gene expression in CD4+CD28+ T cells that characterize lupus flares as well as the aberrant gene expression in CD4+CD28- T cells that promote atherosclerosis.
