Chander Raman, Ph.D. February 2018 Neuroimmunology Chander Raman, Ph.D. February 2018

Overview CNS Anatomy Cells of the CNS – Glia Immune Cell trafficking and lymphatic system CNS diseases - an immunology focus

Overview CNS Anatomy Cells of the CNS – Glia Immune Cell trafficking and lymphatic system CNS diseases - an immunology focus

CNS versus PNS CNS - brain and spinal cord, myelin derived from oligodendrocytes PNS - peripheral nerves myelinated by Schwann cells

Myelination differences in CNS versus PNS One Oligodendrocyte myelinates many axons Many Schwann cells myelinate one axon

White Matter versus Gray Matter Gray matter – nerve cells, cell bodies and vasculature White matter – fiber tracts myelinated by oligodendrocytes

Neurovascular Unit Represents the minimal BBB unit Composed of the endothelial cell tight junctions, basement membrane, pericytes and astrocyte endfeet From Zlokovic, Neuron 57:178, 2008

The CNS Immune System at Homeostasis Prinz and Priller, Nat. Neuroscience 20:136-144

Overview Cells of the CNS – Glia CNS Anatomy Immune Cell trafficking and lymphatic system CNS diseases - an immunology focus

GLIA Oligodendrocytes – wrap neurons and synthesize myelin Astrocytes – Star shaped and wrap most neurosynaptic junctions Microglia – Mobile, phagocytic http://www.networkglia.eu/en/glial_cells

Ontogeny of microglia and physiological roles in CNS development, homeostasis, and plasticity. Salter, M. W. and Stevens Nat. Med. 23:1018-1027 (2017)

Microglia and monocytes have distinct cellular origin Hambardzumyan, D. et al. Nat. Neuroscience 19:20-27 (2016)

Microglia states in health and disease Salter, M. W. and Stevens Nat. Med. 23:1018-1027 (2017)

Overview Immune Cell trafficking and lymphatic system CNS Anatomy Cells of the CNS – Glia Immune Cell trafficking and lymphatic system CNS diseases - an immunology focus

Reich Lab, NIH/NINDS.

Lymphatic drainage of the CNS in humans and in rodents Engelhardt, B. et al. Nat. Immunol. 18:123-131 (2017)

Routes of Leukocyte Entry into CNS Wilson, Weninger and Hunter, J Clin Invest. 2010: 1368–1379

Quintana, F. J. J Clin Invest DOI: 10.1172/JCI95769 (2017) Astrocytes to the rescue! Glia limitans astrocytic endfeet control CNS inflammation Quintana, F. J. J Clin Invest DOI: 10.1172/JCI95769 (2017)

Leukocyte trafficking across the glia limitans into the parenchyma of the brain Wilson, Weninger and Hunter, J Clin Invest. 2010: 1368–1379

Immune surveillance via the choroid plexus Wilson, Weninger and Hunter, J Clin Invest. 2010: 1368–1379

Astrocytes form borders (glia limitans) that serve as functional barriers at interfaces between non-neural tissue and CNS neural parenchyma along blood vessels, meninges and tissue lesions. PBM - parenchymal basement membrane EBM - endothelial basement membrane SAS - subarachnoid space Sofroniew, M.V. 2015. Nat. Rev. Neuroscience 16:249

Origin and turnover of tissue macrophages in healthy CNS pvMΦ - perivascular macrophages mMΦ - meningeal macrophages cpMΦ - choroid-plexus macrophages Prinz, M. et al Nat. Immunol. 18:385-392

The localization and genetic signature of CNS macrophages pvMΦ - perivascular macrophages mMΦ - meningeal macrophages cpMΦ - choroid-plexus macrophages Prinz, M. et al Nat. Immunol. 18:385-392

QA – quisqualate KA - kainate Kelin, R.S. et al. Nat. Immunol. 18:132-141 (2017)

Overview CNS diseases - an immunology focus CNS Anatomy Cells of the CNS – Glia Immune Cell trafficking and lymphatic system CNS diseases - an immunology focus

Peripheral immune cells in the CNS immune system during disease. Prinz and Priller, Nat. Neuroscience 20:136-144

Potential mechanisms of neurological sequelae subsequent to bacterial and fungal meningoencephalitis. Kelin, R.S. et al. Nat. Immunol. 18:132-141 (2017)

Stress-associated changes in neuroimmune function. Wohleb et al. Nat. Rev. Neuroscience 17:497 (2016)

Microglia–neuron interactions in the naive, homeostatic brain and in the stressed or depressed brain. P2X7 - P2X purinoceptor 7 RAGE - receptor for advanced glycation end products Wohleb et al. Nat. Rev. Neuroscience 17:497 (2016)

Immune system dysregulation inside the CNS in early multiple sclerosis Dendrou, C. et al. Nat. Rev. Immunol. 15:545 (2015)

Immune system dysregulation inside the CNS in late multiple sclerosis Dendrou, C. et al. Nat. Rev. Immunol. 15:545 (2015)

Neuroinflammation after traumatic brain injury Simon, D. W. et al Nat. Rev. Neurology 13:171-191 (2017)