- 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.
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|Vo, An; Volpe, Bruce T; Tang, Chris C et al. (2014) Regional brain metabolism in a murine systemic lupus erythematosus model. J Cereb Blood Flow Metab 34:1315-20|
|Chang, Eric H; Frattini, Stephen A; Robbiati, Sergio et al. (2013) Construction of microdrive arrays for chronic neural recordings in awake behaving mice. J Vis Exp :e50470|
|Cohen-Solal, J F G; Diamond, B (2011) [Neuropsychiatric lupus and autoantibodies against ionotropic glutamate receptor (NMDAR)]. Rev Med Interne 32:130-2|
|Cohen-Solal, Joel; Diamond, Betty (2011) Lessons from an anti-DNA autoantibody. Mol Immunol 48:1328-31|
|Bloom, Ona; Cheng, Kai Fan; Cheng, Kai Fen et al. (2011) Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Proc Natl Acad Sci U S A 108:10255-9|
|Diamond, B; Bloom, O; Al Abed, Y et al. (2011) Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus. J Intern Med 269:36-44|
|Aranow, Cynthia; Diamond, Betty; Mackay, Meggan (2010) Glutamate receptor biology and its clinical significance in neuropsychiatric systemic lupus erythematosus. Rheum Dis Clin North Am 36:187-201, x-xi|
|Faust, Thomas W; Chang, Eric H; Kowal, Czeslawa et al. (2010) Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci U S A 107:18569-74|
|Diamond, Betty (2010) Antibodies and the Brain: Lessons from Lupus. J Immunol 185:2637-2640|
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