- PROJECT 3 Anti-DNA, anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, denoted DNRAbs, are present in serum of 30 to 40% patients with systemic lupus (SLE). We have explored the pathogenic potential of these antibodies in protected regions of the brain, specifically the hippocampus and the amygdala and have demonstrated that the antibodies enhance NMDAR activation. Based on new data showing that both patients and mice with DNRAbs have higher serum prolactin levels, we now propose that DNRAbs augment the known NMDAR-mediated release of prolactin by pituitary cells that reside outside the protection of the blood-brain barrier. We will determine whether decoy antigens can neutralize DNRAbs leading to a reduction in serum prolactin levels and a decrease in prolactin-induced autoreactivity. These studies are highly relevant to SLE pathogenesis as prolactin has been shown by us and others to abrogate a B cell tolerance checkpoint that is present as B cells develop from the transitional to the mature na?ve stage and thus to immunocompetence. If our hypothesis is correct, neutralizing DNRAbs will reduce prolactin and diminish pathogenic autoreactivity. The studies are performed in mice but will provide the rationale and the methodology for a clinical trial in patients.
- PROJECT 3 We will confirm that lupus patients with a subset of anti-DNA antibodies that are cross- reactive with the receptor for a neurotransmitter have high prolactin levels and that the antibodies induce prolactin production. Because prolactin reduces a B cell tolerance checkpoint, blocking antibodies that elicit prolactin production might diminish disease severity.
|Huerta, Patricio T; Robbiati, Sergio; Huerta, TomÃ¡s Salvador et al. (2016) Preclinical models of overwhelming sepsis implicate the neural system that encodes contextual fear memory. Mol Med 22:|
|Honig, Gerard; Mader, Simone; Chen, Huiyi et al. (2016) Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve. PLoS One 11:e0144215|
|Vingtdeux, ValÃ©rie; Chang, Eric H; Frattini, Stephen A et al. (2016) CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice. Sci Rep 6:24250|
|Dhawan, Vijay; Robeson, William; Bjelke, David et al. (2015) Human Radiation Dosimetry for the N-Methyl-D-Aspartate Receptor Radioligand 11C-CNS5161. J Nucl Med 56:869-72|
|Huerta, Patricio T; Gibson, Elizabeth L; Rey, Carson et al. (2015) Integrative neuroscience approach to neuropsychiatric lupus. Immunol Res 63:11-7|
|Kowal, Czeslawa; Athanassiou, Andrew; Chen, Huiyi et al. (2015) Maternal antibodies and developing blood-brain barrier. Immunol Res 63:18-25|
|Chang, Eric H; Volpe, Bruce T; Mackay, Meggan et al. (2015) Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor. EBioMedicine 2:755-64|
|Mackay, Meggan; Tang, Chris C; Volpe, Bruce T et al. (2015) Brain metabolism and autoantibody titres predict functional impairment in systemic lupus erythematosus. Lupus Sci Med 2:e000074|
|Jeganathan, Venkatesh; Peeva, Elena; Diamond, Betty (2014) Hormonal milieu at time of B cell activation controls duration of autoantibody response. J Autoimmun 53:46-54|
|Braniste, Viorica; Al-Asmakh, Maha; Kowal, Czeslawa et al. (2014) The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6:263ra158|
Showing the most recent 10 out of 28 publications