2014 B cells, Target Identification, General Immune System Function, Human Lupus Biology
2001 Central Nervous System
Autoantibodies and prolactin participate in a positive feedback loop
The Study And What It Means To Patients
Approximately 25 percent of patients with lupus have increased blood levels of the hormone prolactin, best known for its role in breast milk production. Prolactin is also known to make autoimmune diseases worse. We are testing our novel idea that lupus autoantibodies cause increased prolactin levels. If we can prove that lupus autoantibodies drive up prolactin levels and increase the severity of lupus, it may be possible to use existing drugs that decrease prolactin levels to limit the extent of the disease.
B cells from patients with lupus drive the development of the disease by producing antibodies that react with the body’s own DNA. In earlier LRI-funded research, we discovered that some of these anti-DNA antibodies are also able to interact with a neurotransmitter receptor in the brain called N-Methyl-D-aspartate receptor (NMDAR). As triggering NMDAR is known to lead to prolactin production, we want to explore whether these elements link together to establish a vicious cycle that helps drive disease: that is, do specific anti-DNA antibodies trigger increased prolactin production by triggering NMDAR, leading to more autoantibodies that target the body’s own tissues and further trigger NMDAR.
Since we know that prolactin makes lupus worse, understanding the reasons for the high levels of prolactin present in ~25% of SLE patients has potential implications for developing a treatment. It may be possible to decrease the number of harmful B cells, thereby limiting the extent of the disease, by blocking the interaction of the anti-DNA antibodies with NMDAR and reducing prolactin levels. Additionally, monitoring prolactin levels could be useful in showing whether a therapy has led to a decrease in harmful antibodies.
Some anti-DNA antibodies cross-react with N-Methyl-D-Aspartate receptors (NMDARs) and enhance their activation. NMDARs are known to regulate prolactin synthesis and secretion. We hypothesize that anti-DNA/NMDAR cross-reactive antibodies increase serum prolactin. Approximately 25% of lupus patients have increased prolactin levels which, in mouse studies, can abrogate B-cell tolerance. We propose to confirm that these antibodies establish an amplification loop in SLE.
Some ten years ago, scientist Dr. Betty Diamond came to the Lupus Research Institute with a critical clinical question that could only be answered with molecular research – why do four out of five people with lupus suffer with some type of neuropsychiatric difficulty? With funding granted on the merit of her hypothesis, Dr. Diamond found her answer. Based on that research, she is now developing a novel drug-like molecule that could lead to a treatment for lupus.
Dr. Diamond’s original LRI-supported research discovery found that a particular type of lupus antibody found in the brains of lupus patients can attach to and kill nerve cells in the brain, causing neurological and cognitive difficulties. Dr. Diamond, together with Dr. Yousef Al-Abed and other colleagues at the Feinstein Institute of Medical Research in New York, recently published a paper in the Proceedings of the National Academy of Sciences describing how their new molecule neutralizes (counteracts) the specific type of nerve-damaging lupus autoantibody she had identified years before. In this recent study, the new molecule protected brain cells in mice from damage by lupus autoantibodies.
“The LRI was the first organization to fund studies of this model of neuropsychiatric lupus,” said Dr. Diamond. “With the Institute’s grant as well as subsequent funding from the NIH, we provided the first molecular explanation of how the central nervous system is attacked in lupus. We are even more excited to have now developed a molecule that can block that attack.”
Potential for Patients
Like any breakthrough, this discovery did not happen in a vacuum. Other research teams have been able to neutralize the autoantibodies Dr. Diamond originally identified by using a peptide (a short chain of amino acids) that mimics the receptor the autoantibodies bind to. But its potential as a treatment is limited because the peptide cannot be taken orally and can inadvertently activate the immune system. Dr. Diamond’s group designed their new molecule with a similar shape as the earlier peptide, but to overcome its limitations, used distinct chemical building blocks so that the molecule can be absorbed orally and avoid triggering the immune system.
The Feinstein researchers stress that the molecule is still at an early stage of drug development. They will share a $571,610 NIH grant with Biomedical Research Models Inc. to test the molecule to see if it is safe for clinical trials with patients.
Cognition and immunity; antibody impairs memory. Immunity. 2004 Aug;21(2):179-88. Kowal C, DeGiorgio LA, Nakaoka T, Hetherington H, Huerta PT, Diamond B, Volpe BT.
Immunity and behavior: antibodies alter emotion. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):678-83. Huerta PT, Kowal C, DeGiorgio LA, Volpe BT, Diamond B.
Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol. 2005 May;12(5):392-8. Omdal R, Brokstad K, Waterloo K, Koldingsnes W, Jonsson R, Mellgren SI.
Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus. Ann Rheum Dis. 2005 Aug;64(8):1210-3. Husebye ES, Sthoeger ZM, Dayan M, Zinger H, Elbirt D, Levite M, Mozes E.
Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Bloom O, Cheng KF, He M, Papatheodorou A, Volpe BT, Diamond B, Al-Abed Y. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10255-9. Epub 2011 Jun 6.
Dr. Diamond won a $6.5 million program grant from the NIH to build on more strategies for dealing with this devastating lupus-related development.
Rev. March 2012