- 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.
|Mader, Simone; Brimberg, Lior; Soltys, John N et al. (2018) Mutations of Recombinant Aquaporin-4 Antibody in the Fc Domain Can Impair Complement-Dependent Cellular Cytotoxicity and Transplacental Transport. Front Immunol 9:1599|
|Suurmond, Jolien; Atisha-Fregoso, Yemil; Marasco, Emiliano et al. (2018) Loss of an IgG plasma cell checkpoint in patients with lupus. J Allergy Clin Immunol :|
|Nestor, Jacquelyn; Arinuma, Yoshiyuki; Huerta, Tomás S et al. (2018) Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J Exp Med 215:2554-2566|
|Kim, Sook Young; Son, Myoungsun; Lee, Sang Eun et al. (2018) High-Mobility Group Box 1-Induced Complement Activation Causes Sterile Inflammation. Front Immunol 9:705|
|Malkiel, Susan; Barlev, Ashley N; Atisha-Fregoso, Yemil et al. (2018) Plasma Cell Differentiation Pathways in Systemic Lupus Erythematosus. Front Immunol 9:427|
|VanPatten, Sonya; Sun, Shan; He, Mingzhu et al. (2016) Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies. J Med Chem 59:8859-8867|
|Vingtdeux, Valérie; Chang, Eric H; Frattini, Stephen A et al. (2016) CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice. Sci Rep 6:24250|
|Brimberg, L; Mader, S; Jeganathan, V et al. (2016) Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice. Mol Psychiatry 21:1663-1671|
|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|
|Malkiel, Susan; Jeganathan, Venkatesh; Wolfson, Stacey et al. (2016) Checkpoints for Autoreactive B Cells in the Peripheral Blood of Lupus Patients Assessed by Flow Cytometry. Arthritis Rheumatol 68:2210-20|
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