Browsing by Subject "lupus"
Now showing 1 - 4 of 4
- Results Per Page
- Sort Options
Item Dysfunctional neuroimmune pathways promote the development and maintenance of lupus hypertension(2020-05) Pham, Grace S.; Mathis, Keisa W.; Rickards, Caroline A.; Goulopoulou, Styliani; Cunningham, J. Thomas; Ma, Rong; Mathew, Stephen O.Hypertension afflicts nearly half of the adults in the United States and the majority of cases have no known cause. Chronic inflammation has been implicated in the development and maintenance of hypertension, and autoimmunity may comprise one of its sources. Hypertension is highly prevalent in the autoimmune disease systemic lupus erythematosus (SLE), in which chronic aberrant inflammation may be a causative factor. Endogenous neuroimmune pathways, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cholinergic anti-inflammatory pathway, likely contribute to this phenomenon. The HPA axis is a classical neuroimmune mechanism that senses peripheral inflammation via afferent vagal fibers, culminating in the release of the anti-inflammatory hormone cortisol. Previous studies have characterized HPA axis dysfunction in SLE, but less is known about how this dysregulation specifically impacts the hypertension that occurs in the setting of SLE. A second neuroimmune interaction, the cholinergic anti-inflammatory pathway, is an efferent vagus nerve-to-spleen mechanism that relies on T cell-produced acetylcholine to quell inflammation in acute settings and may be hypoactive in chronic inflammatory diseases like SLE. Notably, both of these neuroimmune mechanisms depend on vagus nerve function, identifying the vagus as a potential target for neuromodulation. Furthermore, the relationship between chronic inflammation and hypertension validates the investigation of neuroimmune pathway dysfunction towards novel mechanisms of hypertension. Herewithin, the HPA axis and cholinergic anti-inflammatory pathway are investigated using the well-established NZBWF1 mouse model of lupus hypertension. Our findings are that (1) administration of an inflammatory stimulus that activates vagal afferents elicits comparable neuronal activation in the paraventricular nucleus of the hypothalamus, compared to control mice, despite heightened peripheral inflammation; (2) amplification of efferent vagus nerve activity reduces blood pressure and renal inflammation; and (3) chronic unilateral vagotomy paradoxically results in decreased blood pressure and renal inflammation. Taken together, these findings identify dysfunction in two neuroimmune pathways while demonstrating that interventions targeting these pathways may have therapeutic benefits in lupus hypertension. In terms of future impact, these results may promote continuing inquiry in a more recently discovered neuroimmune pathway (i.e., cholinergic anti-inflammatory pathway), as well as reinstate curiosity in an older, abandoned area of research (i.e., HPA).Item Expression of CSI and 2B4 in Human Lupus Erythematosus and Transcriptional Regulation of CSI Gene(2010-07-01) Kim, Jongrok; Porunelloor MathewSystemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by production of pathogenic autoantibodies that affect multiple organs. Signaling lymphocyte activation molecule (SLAM) family receptors play critical roles in the regulation of hematopoietic cells, and polymorphisms in these receptors were found to be associated with susceptibility to SLE. In addition, the differential expression of splice variants of one member of SLAM family receptors was shown to be responsible for lupus development in mice. Since the important roles of SLAM family receptors 2B4 and CS1 in immune regulation are expanding, we compared the expression of 2B4 and CS1 in peripheral blood mononuclear cells (PBMCs) from SLE patients with those of healthy individuals. While alterations of the expression of 2B4 and CS1 were observed in SLE, most strikingly, a linear relationship was found between the proportion of CS1-expressing B cells and SLE disease activity index (SLEDAI). In particular, CS1-high expressing B cells were phenotypically similar with recently described plasmablasts, which were also shown to correlate with disease severity. Since CS1 is self-ligand and homotypic interaction of CS1-expressing B cells can trigger expansion of B cells, these results emphasize the role of CS1 in B cell-mediated diseases. Therefore, the transcriptional regulation of CS1 gene was investigated. DNA elements at -405 to +92 region of the CS1 promoter positively regulated CS1 expression. Interestingly, electrophoretic mobility shift and chromatin immunoprecipitation assays revealed that the plasma cell specific-transcription factor Blimp-1 binds to the CS1 promoter region. Further analysis of expression and transcriptional regulation of CS1 in B cells will provide valuable information for the treatment of B-cell mediated diseases such as SLE and multiple myeloma.Item Function and Regulation of the Natural Killer Cell Receptor 2B4 (CD244)(2005-05-01) Vaidya, Swapnil V.; Porunelloor A. Mathew; Richard Easom; Hriday DasThe purpose of these studies was to investigate two issues related to the natural killer (NK) cell receptor, 2B4 (CD244) – its in vivo function and transcriptional regulation. In previous in vitro studies, ligation of 2B4 with a monoclonal antibody enhanced the cytotoxicity of NK and CD8 T cells against various tumor cell lines, indicating that 2B4 is an activating receptor. To study the role of 2B4 in vivo, 2B4 deficient (2B4-/-) mice were used. The initial characterization of the 2B4-/- mice indicate a thymic developmental defect with an increase in the immature CD4-/CD8- population in the thyme of female but not male mice. NK cells from the 2B4-/- mice were impaired in activation by IL-2 as compared to wild type NK cells. These results suggest a role of 2B4 in lymphoid development. The in vivo role of 2B4 in tumor rejection was studied in a mouse tumor model in which melanoma cells were injected intravenously and pulmonary metastases enumerated 14 days later. The murine melanoma cell line, B16, was stably transfected with CD48, the counter-receptor for 2B4. Using CD48+ and CD48- B16 cells in tumor experiments indicated that 2B4 functioned as an inhibitory receptor. In addition, a gender-specific role of 2B4 in the rejection of B16 melanoma cells was discovered. 2B4-/- male mice cleared B16 cells more efficiently than wild type male mice, while female 2B4-/- mice were impaired in controlling tumor growth as compared to wild type female mice. In vitro and in vivo studies indicate a complex role for NK cells in the mechanism of this gender effect. Several studies have shown that the expression of 2B4 is upregulated during viral infections and under certain cytokine stimulation. Previously, it has been shown activator protein-1 (AP-1) plays an important role in the transcription of the 2B4 gene. In this study an Ets transcription factor was shown to upregulate the transcription of the gene. This element functions in an AP-1 dependent manner. Stimulation of surface 2B4 down-regulates its own expression by decreasing the activity of the Ets element in the 2B4 promoter. These studies identify a role of 2B4 in lymphoid development and tumor rejection in vivo. The gender-specific defect in 2B4 knock-out mice implicates its role in lupus. The transcriptional studies provide insights into the regulation of 2B4 gene.Item Should Renal Inflammation Be Targeted While Treating Hypertension?(Frontiers Media S.A., 2022-06-13) Chaudhari, Sarika; Pham, Grace S.; Brooks, Calvin D.; Dinh, Viet Q.; Young-Stubbs, Cassandra M.; Shimoura, Caroline G.; Mathis, Keisa W.Despite extensive research and a plethora of therapeutic options, hypertension continues to be a global burden. Understanding of the pathological roles of known and underexplored cellular and molecular pathways in the development and maintenance of hypertension is critical to advance the field. Immune system overactivation and inflammation in the kidneys are proposed alternative mechanisms of hypertension, and resistant hypertension. Consideration of the pathophysiology of hypertension in chronic inflammatory conditions such as autoimmune diseases, in which patients present with autoimmune-mediated kidney inflammation as well as hypertension, may reveal possible contributors and novel therapeutic targets. In this review, we 1) summarize current therapies used to control blood pressure and their known effects on inflammation; 2) provide evidence on the need to target renal inflammation, specifically, and especially when first-line and combinatory treatment efforts fail; and 3) discuss the efficacy of therapies used to treat autoimmune diseases with a hypertension/renal component. We aim to elucidate the potential of targeting renal inflammation in certain subsets of patients resistant to current therapies.