Preserving the Brain: Immune Cells in the MS Nervous System
October 05, 2022ID8137
To CiteDCA Citation Guide
- 00:05To put a historical perspective on
- 00:08the dramatic advances in biology,
- 00:10it's been during my lifetime that we
- 00:13learned the function of DNA as a first
- 00:15year student in college. In 1970,
- 00:17I saw a patient with multiple sclerosis,
- 00:20which at the time were thought to
- 00:23be mediated by the immune system.
- 00:25They were virtually no treatments
- 00:27I knew then. I wanted to dedicate
- 00:29my career to understanding.
- 00:31Disease and discover effective treatments.
- 00:34We've come a long way since the
- 00:36two major types of immune cells,
- 00:38T cells and B cells,
- 00:39were discovered around the time
- 00:41I saw my first Ms patient.
- 00:43There is a technique allowing us
- 00:45to visualize many different immune
- 00:47cell populations in the brain.
- 00:49So David, what are we looking
- 00:50at here? This is a Ms lesion,
- 00:52and all of these colored
- 00:55objects are individual cells
- 00:56that have different functions.
- 00:58And if you zoom in.
- 01:01Like so you see, for example,
- 01:03a immune cell at cell that directs
- 01:06a scavenger cell to devour mile.
- 01:09In Ms Research, an important event would
- 01:12allow us to deeply characterize those
- 01:14immune T cells and B cells without bias.
- 01:17We can now use a dramatic new technology
- 01:20called single cell RNA sequencing allows us
- 01:23to interrogate each individual immune cell.
- 01:26Examining the brain itself is too invasive,
- 01:29but we can access immune cells in
- 01:31the brain by examining spinal fluid,
- 01:33the liquid around the brain and
- 01:35spinal cord that tells us what
- 01:37immune cells are in the brain.
- 01:38We extract spinal fluid from a patient
- 01:41using a Spinal Tap by inserting
- 01:43a needle between the vertebrae
- 01:45and then collecting the fluid.
- 01:48Once extracted,
- 01:48the spinal fluid is rushed to the lab,
- 01:51where it's spun down to collect the cells,
- 01:53then brought to the 10X machine.
- 01:59We encapsulate each single T cell into
- 02:01a functionalized gel B as bar coded and
- 02:04mixed with enzymes and oils to create
- 02:06single cell microdroplets or gems.
- 02:08We then perform a chemical reaction
- 02:10to amplify the nucleic acid that
- 02:12codes for proteins that define each
- 02:14cell type to learn their function.
- 02:16The elegance of the technology is that
- 02:19we can identify cellular subtypes
- 02:21and rare cells with little bias,
- 02:23giving a big picture of the
- 02:26biology underlying the disease.
- 02:27This is what. We have discovered.
- 02:31Here we have a snapshot of the
- 02:33different and mean populations and the
- 02:35spinal fluid of a healthy subject,
- 02:37the blue dots,
- 02:38each representing immune cells
- 02:40with RNA signatures of the blood.
- 02:42The yellow dots are cells with
- 02:44RNA signatures of spinal fluid.
- 02:46As T cells traffic into the spinal fluid,
- 02:49they transition toward RNA signature.
- 02:51That's more nervous system like
- 02:53which is in green.
- 02:56Armed with what happens
- 02:57in healthy subjects,
- 02:59we can now look at patients with Ms.
- 03:01The lighter the color,
- 03:02the more the difference.
- 03:03Here we've identified the
- 03:05fundamental gene signatures
- 03:07that are different in patients
- 03:09with Ms an environmental event
- 03:11like an infection by common virus
- 03:14such as Epstein Barr virus or BV,
- 03:16may lead to the activation of
- 03:19autoreactive T cells recognizing myelin.
- 03:22These activated T cells that
- 03:23migrate into the brain where they.
- 03:25Cause inflammation.
- 03:27Blocking their migration with monoclonal
- 03:30antibodies markedly decreases.
- 03:32Ms attacks.
- 03:33Multiple sclerosis is a
- 03:35genetically mediated disease.
- 03:37We've identified 233 common genetic variants,
- 03:41each with a small effect on disease risk,
- 03:43but together lead to the disease.
- 03:45Majority of these common variants
- 03:47are controlling immune function and
- 03:49together contribute to a lower threshold
- 03:51for activating the immune system.
- 03:53It appears that B cells are critical.
- 03:55The activation of T cells.
- 03:57Perhaps related to the EBV virus,
- 04:00which infects B cells.
- 04:01Now the bleeding B cells also has
- 04:04a dramatic effect on stopping
- 04:07attacks in early disease.
- 04:09Here the monoclonal antibody is
- 04:11given to a patient every six months.
- 04:14We're now engaged in a clinical trial
- 04:16using B cell depletion at the very
- 04:19early stages of disease before there
- 04:21are any clinical manifestations.
- 04:23What advances that have been made since
- 04:25I saw my first patient with Ms Back in 1970.
- 04:28Back then we didn't know if the
- 04:31brain inflammation was secondary.
- 04:33Or causing Ms we now know the
- 04:35inflammation is causing the disease
- 04:38as immune modulation has dramatic
- 04:40effects on disease progression.
- 04:42We now know a significant number
- 04:44of the genes that cause Ms.
- 04:46They directly implicate the immune
- 04:48system and initiating the disease.
- 04:50Most importantly,
- 04:51in 1970 we had no treatments for
- 04:53Ms Now we have highly effective
- 04:56treatments that stop disease flare ups.
- 04:59Do we know the cause of Ms while
- 05:01science does not truly prove causality.
- 05:03We make models that are constantly
- 05:06refined and tested by clinical trials.
- 05:08These models provide the most
- 05:11convincing evidence for causality.
- 05:12While we have a good working model
- 05:15for early relapsing mitting Ms,
- 05:16we have little insight into the
- 05:18progressive phase of the disease.
- 05:21We also don't know yet whether
- 05:23early treatment would be cell
- 05:25depletion prevents evolution to
- 05:27the progressive form of Ms.
- 05:29However, our examination of spinal fluid,
- 05:31these powerful new single cell
- 05:33technologies has revealed
- 05:35previously unknown pathways found
- 05:36in the infiltrating immune cells
- 05:38that are causing the disease.
- 05:40It will take years to put these new
- 05:43experiments into a more refined model of Ms,
- 05:45but this is an incredibly exciting time
- 05:48in the study of this disease and of neuro.
- 05:51Degeneration.