Jonathan Kipnis

Jonathan Kipnis is a neuroscientist, immunologist, and professor of pathology and immunology at the Washington University School of Medicine.[1] His lab studies interactions between the immune system and nervous system.[2] He is best known for his lab's discovery of meningeal lymphatic vessels in humans and mice, which has impacted research on neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis,[3] neuropsychiatric disorders, such as anxiety, and neurodevelopmental disorders such as autism and Rett syndrome.

Jonathan Kipnis
NationalityIsraeli, American
Alma mater
Known fordiscovery of brain lymphatic vessels
Scientific career
FieldsNeuroimmunology
Institutions
Doctoral advisorMichal Schwartz
WebsiteLab website

Early life and education

Kipnis was born into a Jewish family in Tbilisi, Georgia. His father and maternal grandmother were both physicians and his mother was an academic with a focus in Russian literature and language. Growing up surrounded by physicians, Kipnis knew from a young age that he wanted to cure diseases.[4] With this goal in mind, Kipnis pursued his undergraduate degree in biology at Tel Aviv University in Ramat Aviv, Israel.[5] He completed his Bachelors of Science in 1998, and went on to conduct his Master's in neurobiology at the Weizmann Institute of Science in Rehovot, Israel. He obtained his Master's in 1999.[5]

For his graduate training, Kipnis remained at the Weizmann Institute of Science. Interested in the field of cancer immunology, Kipnis first worked with Moshe Oren.[6] After attending a lecture by Michal Schwartz, a leader in the field of neuroimmunology, he became fascinated by the intersection of immunology and neuroscience and decided to pursue a PhD in neuroimmunology.[5] Kipnis joined the lab of Michal Schwartz the year that they discovered the therapeutic benefit of T cells in spinal chord and brain injury, a pioneering finding that began the study of the protective roles of autoimmunity in CNS disease.[7][8] This was the beginning of Kipnis' career exploring the connections between the brain and the immune system.[9]

In the Schwartz Lab, Kipnis' work focused on T cell based autoimmune reactions in CNS injury and neurodegeneration.[10] Kipnis elucidated the pleiotropic roles of regulatory T cells in CNS injury versus CNS homeostasis.[11] By depleting naturally occurring regulatory T cells after CNS injury, Kipnis was able to improve neuronal survival in mice.[11] However, by up-regulating effector autoimmune T cells through immunization with CNS antigen, Kipnis was able to improve recovery after CNS injury. These results showed that the immune system's intrinsic mechanisms to protect against autoimmunity, might not be beneficial when insults demand autoimmune effector function for tissue maintenance.[11] In 2002, Kipnis was awarded the Sir Charles Clore Scholarship and Award of Excellence in doctoral studies, and then in 2004 was awarded the Distinguished Prize for Excellence in doctoral studies by the Israeli Parliament, Knesset.[12]

Kipnis remained at the Weizmann for his postdoctoral training in Schwartz's lab. It was during his postdoc that Kipnis, along with other members of the Schwartz lab, discovered that brain antigen specific T cells play a role in neurogenesis and cognitive functions, such as memory and spatial learning.[13] This was one of the seminal findings showing that the immune system, through T cells, plays a role in cognition and brain homeostasis.[7]

Career and research

Kipnis joined the University of Virginia School of Medicine (UVA) in 2007, where he later became a Harrison Distinguished Professor and chair of the department of neuroscience. He also directed the Center for Brain Immunology and Glia (BIG Center) at UVA.[12] In 2019, he accepted an offer to join the Washington University School of Medicine faculty via the BJC Investigators Program. He is primarily appointed in the department of pathology and immunology, and secondarily appointed in neurology, neuroscience, and neurosurgery.[1] Kipnis is also a Gutenberg Forschungskolleg Fellow and supervises a working group at the University of Mainz.[14]

Meningeal lymphatic vessels

Kipnis is credited with the 2014 discovery of meningeal lymphatic vessels, a recently discovered network of conventional lymphatic vessels located parallel to the dural sinuses and meningeal arteries of the mammalian central nervous system (CNS). As a part of the lymphatic system, the meningeal lymphatics are responsible for draining immune cells, small molecules, and excess fluid from the CNS and into the deep cervical lymph nodes.

While it was initially believed that both the brain and meninges were devoid of lymphatic vasculature, the landmark Nature paper by Jonathan Kipnis and his postdoctoral fellow Antoine Louveau was published in 2015. By 2017, this paper was cited nearly 600 times, putting it in the 99th percentile for articles published that year.[15]

His discovery of meningeal lymphatic vessels has attracted attention from many sources, and was touted as a scientific breakthrough in lists such as Scientific American's "Top 10 Science Stories of 2015", Science Magazine's "Breakthrough of the Year", Huffington Post's "Eight Fascinating Things We Learned About the Mind in 2015" and the National Institutes of Health's director Francis Collins year end review.[2][16] Business Insider highlighted this as the biggest discovery ever made in Virginia.[17]

Cytokines and behavior

Other high-profile research has included the 2015 discovery that the immune system directly affects social behavior and that IFN-gamma is necessary for social development.[18][19] This expands upon his work as a graduate student, when he discovered that mice lacking T-cells had cognitive impairments.[12][20]

Kipnis' lab also elucidated the role of meningeal gamma delta (γδ) T cells in anxiety behavior.[21][22] They found that γδ T cells are resident in high numbers in the meningeal immune compartment, and they actively transcribe the cytokine IL-17a at homeostasis.[23] Kipnis' team further discovered that the release of IL-17a from γδ T cells was correlated with anxiety behavior in mice. They found high expression of IL-17a receptor in the prefrontal cortex glutamatergic neurons, and when they knocked down IL-17a receptor in cortical glutamatergic neurons, this recapitulated the anxiety phenotype in mice.[24]

He is the senior author of a 2015 paper describing how CD4+ T-cells protect and repair neurons after injury to the spinal cord and brain.[25] A collaboration with Kodi Ravichandran characterized the generation of neurons in adult brains and the removal of dead neurons by phagocytic cells.[26]

In 2016, he was the senior author on a paper identifying type 2 innate lymphocytes in the meninges near the lymphatic vessels his lab previously discovered. These cells have previously have been found in the gut, which suggests a link between the brain and the microbiome.[27] In mice, these meningeal ILC2 cells were activated by IL-33 after spinal cord injury.[28]

Awards and honors

Kipnis' work has been funded by the Simons Foundation Autism Research Initiative,[29] National Institutes of Health, the Hartwell Foundation, and the Cure Alzheimer's Fund.[12] In 2018, he was awarded the NIH's prestigious Director's Pioneer Award and $5.6 million in additional research funding.[30]

  • 2002 - Sir Charles Clore scholarship and award of excellence in doctoral studies
  • 2002 Representative of Israeli Student Delegation for the International Summit of the American Academy of Achievement
  • 2003 Representative of Israeli Student Delegation, International Summit for Nobel Prize Laureates in Medicine
  • 2004 Distinguished Prize for excellence in doctoral studies awarded by the Israeli Parliament (Knesset)
  • 2004 Prize of excellence for doctoral studies awarded by the Feinberg Graduate School, Weizmann Institute of Science,
  • 2006 Vada Kinman Oldfield Alzheimer’s Research Award, University of Nebraska Medical Center
  • 2011 Robert Ader New Investigator Award
  • 2011 PsychoNeuroImmunology Research Society (PNIRS)
  • 2012 Jordi Folch-Pi award, American Society for Neurochemistry
  • 2014 Distinguished Research Career Development Award, University of Virginia
  • 2015 Gutenberg Research College (GRC) fellowship, Johannes Gutenberg University of Mainz
  • 2016 Harrison Foundation Distinguished Teaching Professorship in Neuroscience
  • 2016 MIND Institute Distinguished Lecturer.[31]
  • 2018 NIH Director’s Pioneer Award [32]
  • 2020 NIH/NIA MERIT Award

Select publications
  • Alves de Lima K, Rustenhoven J, Da Mesquita S, Wall M, Salvador AF, Smirnov I, Martelossi Cebinelli G, Mamuladze T, Baker W, Papadopoulos Z, Lopes MB, Cao WS, Xie XS, Herz J, Kipnis J. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol. 2020 Nov;21(11):1421-1429. doi: 10.1038/s41590-020-0776-4. Epub 2020 Sep 14. PMID 32929273.[33]
  • Rustenhoven J, Kipnis J. Bypassing the blood-brain barrier. Science. 2019 Dec 20;366(6472):1448-1449. doi: 10.1126/science.aay0479. PMID 31857468.[34]
  • Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41. doi:10.1038/nature14432.
  • Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, Peerzade SN, Chen H, Lee KS, Scott MM, Beenhakker MP, Litvak V, Kipnis J. (2016) Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature Jul 13;535(7612):425-429. doi:10.1038/nature18626.
  • Sandro Da Mesquita, Antoine Louveau, Andrea Vaccari, Igor Smirnov, R. Chase Cornelison, Kathryn M. Kingsmore, Christian Contarino, Suna Onengut-Gumuscu, Emily Farber, Daniel Raper, Kenneth E. Viar, Romie D. Powell, Wendy Baker, Nisha Dabhi, Robin Bai, Rui Cao, Song Hu, Stephen S. Rich, Jennifer M. Munson, M. Beatriz Lopes, Christopher C. Overall, Scott T. Acton & Jonathan Kipnis. (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. Aug;560(7717):185-191 doi: 10.1038/s41586-018-0368-8

References
  1. Tamara Bhandari (2019-11-13). "Kipnis named BJC Investigator". Washington University School of Medicine in St. Louis. Retrieved 2020-01-15.
  2. "NIH, Scientific American, Science salute UVA brain discovery". Retrieved 22 December 2016.
  3. "Lymphatic Vessels in Brain Provide New Route to Treat MS | GEN". GEN. Retrieved 4 October 2018.
  4. "Jonathan Kipnis, PhD, recipient of the 2018 Pioneer in Medicine - YouTube". www.youtube.com. Retrieved 2021-01-04.
  5. "Jonathan Kipnis, PhD | Pathology & Immunology | Washington University in St. Louis". pathology.wustl.edu. Retrieved 2021-01-04.
  6. "Moshe Oren". Rett Syndrome Research Trust Blog. Retrieved 2021-01-04.
  7. "The vital link between your immune system and brain". www.macleans.ca. Retrieved 2021-01-04.
  8. "Immune System Maintains Brain Health - The Scientist Magazine". Retrieved 22 December 2016.
  9. "Jonathan Kipnis on discovering the brain's lymphatic system". Neuro Central. Retrieved 2021-01-04.
  10. Schwartz, Michal; Kipnis, Jonathan (2005-06-15). "Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases". Journal of the Neurological Sciences. 233 (1–2): 163–166. doi:10.1016/j.jns.2005.03.014. ISSN 0022-510X. PMID 15949502.
  11. Kipnis, Jonathan; Mizrahi, Tal; Hauben, Ehud; Shaked, Iftach; Shevach, Ethan; Schwartz, Michal (2002-11-26). "Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system". Proceedings of the National Academy of Sciences of the United States of America. 99 (24): 15620–15625. doi:10.1073/pnas.232565399. ISSN 0027-8424. PMID 12429857.
  12. "Jonathan Kipnis, Ph.D." Retrieved 22 December 2016.
  13. Ziv, Yaniv; Ron, Noga; Butovsky, Oleg; Landa, Gennady; Sudai, Einav; Greenberg, Nadav; Cohen, Hagit; Kipnis, Jonathan; Schwartz, Michal (February 2006). "Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood". Nature Neuroscience. 9 (2): 268–275. doi:10.1038/nn1629. ISSN 1097-6256. PMID 16415867.
  14. "Newsdetail - Universitätsmedizin Mainz - 165". Retrieved 22 December 2016.
  15. Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J.; Eccles, Jacob D.; Rouhani, Sherin J.; Peske, J. David; Derecki, Noel C.; Castle, David; Mandell, James W.; Lee, Kevin S.; Harris, Tajie H.; Kipnis, Jonathan (16 July 2015). "Structural and functional features of central nervous system lymphatic vessels". Nature. 523 (7560): 337–341. doi:10.1038/nature14432. PMC 4506234. PMID 26030524.
  16. "Media coverage of our discoveries". Retrieved 22 December 2016.
  17. http://www.businessinsider.com/scientific-discovery-in-50-states-2017-6/#virginia-scientists-discovered-an-unexpected-connection-to-the-brain-that-will-rewrite-textbooks-46
  18. "Shocking New Role Found for the Immune System: Controlling Social Interactions". 13 July 2016. Retrieved 22 December 2016.
  19. Filiano, Anthony J.; Xu, Yang; Tustison, Nicholas J.; Marsh, Rachel L.; Baker, Wendy; Smirnov, Igor; Overall, Christopher C.; Gadani, Sachin P.; Turner, Stephen D.; Weng, Zhiping; Peerzade, Sayeda Najamussahar; Chen, Hao; Lee, Kevin S.; Scott, Michael M.; Beenhakker, Mark P.; Litvak, Vladimir; Kipnis, Jonathan (21 July 2016). "Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour". Nature. 535 (7612): 425–429. doi:10.1038/nature18626. PMC 4961620. PMID 27409813.
  20. Kipnis, Jonathan; Cohen, Hagit; Cardon, Michal; Ziv, Yaniv; Schwartz, Michal (25 May 2004). "T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions". PNAS. 101 (21): 8180–8185. doi:10.1073/pnas.0402268101. PMC 419577. PMID 15141078.
  21. Alves de Lima, Kalil; Rustenhoven, Justin; Da Mesquita, Sandro; Wall, Morgan; Salvador, Andrea Francesca; Smirnov, Igor; Martelossi Cebinelli, Guilherme; Mamuladze, Tornike; Baker, Wendy; Papadopoulos, Zach; Lopes, Maria Beatriz (November 2020). "Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons". Nature Immunology. 21 (11): 1421–1429. doi:10.1038/s41590-020-0776-4. ISSN 1529-2916.
  22. "Immune Cell Signaling to the Brain Regulates Anxiety-Like Behaviors". GEN - Genetic Engineering and Biotechnology News. 2020-09-16. Retrieved 2021-01-03.
  23. "Immune system may trigger anxiety in response to infection". www.medicalnewstoday.com. 2020-09-23. Retrieved 2021-01-03.
  24. "Immune Cell and Its Cytokine Control Exploratory Behavior in Mice". The Scientist Magazine®. Retrieved 2021-01-03.
  25. Walsh, James T.; Hendrix, Sven; Boato, Francesco; Smirnov, Igor; Zheng, Jingjing; Lukens, John R.; Gadani, Sachin; Hechler, Daniel; Gölz, Greta; Rosenberger, Karen; Kammertöns, Thomas; Vogt, Johannes; Vogelaar, Christina; Siffrin, Volker; Radjavi, Ali; Fernandez-Castaneda, Anthony; Gaultier, Alban; Gold, Ralf; Kanneganti, Thirumala-Devi; Nitsch, Robert; Zipp, Frauke; Kipnis, Jonathan (2 February 2015). "MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4". J Clin Invest. 125 (2): 699–714. doi:10.1172/JCI76210. PMC 4319416. PMID 25607842.
  26. "Researchers helps explain how the adult brain cleans out dead brain cells and produces new ones". 10 August 2011. Retrieved 22 December 2016.
  27. "UVA discovers powerful defenders of the brain -- with big implications for disease". Retrieved 22 December 2016.
  28. Gadani, Sachin P.; Smirnov, Igor; Smith, Ashtyn T.; Overall, Christopher C.; Kipnis, Jonathan (16 December 2016). "Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury". The Journal of Experimental Medicine. 214 (2): 285–296. doi:10.1084/jem.20161982. PMC 5294864. PMID 27994070.
  29. "SFARI". Retrieved 22 December 2016.
  30. Staff, News. "UVA researcher wins national award, funding". Retrieved 4 October 2018.
  31. (PDF). January 13, 2016 http://media.mindinstitute.org/video/graphics/dls/2016/kipnis_bioabstract.pdf. Retrieved 2020-01-15. Missing or empty |title= (help)
  32. "UVA's Jonathan Kipnis Receives Prestigious NIH Director's Pioneer Award". UVA Today. 2018-10-02. Retrieved 2021-01-04.
  33. Alves de Lima, Kalil; Rustenhoven, Justin; Da Mesquita, Sandro; Wall, Morgan; Salvador, Andrea Francesca; Smirnov, Igor; Martelossi Cebinelli, Guilherme; Mamuladze, Tornike; Baker, Wendy; Papadopoulos, Zach; Lopes, Maria Beatriz (November 2020). "Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons". Nature Immunology. 21 (11): 1421–1429. doi:10.1038/s41590-020-0776-4. ISSN 1529-2916. PMID 32929273.
  34. Rustenhoven, Justin; Kipnis, Jonathan (20 December 2019). "Bypassing the blood-brain barrier". Science. 366 (6472): 1448–1449. doi:10.1126/science.aay0479. ISSN 1095-9203. PMID 31857468.
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