Lupus, Autoimmune Inflamation & Retroelements - The Gehlhausen Lab at Yale School of Medicine

Transcript

• 00:05The skin itself is a barrier to the external world.
• 00:09You need to be able to respond to things like physical trauma, to pathogens,
• 00:14and so it has a remarkable ability to both generate
• 00:17and resolve these kind of inflammatory contexts.
• 00:21But in the setting of autoimmunity, you're no longer able to turn off that switch.
• 00:27At a fundamental level, the body is confused
• 00:30and recognizing something as a virus.
• 00:39I focus on cutaneous lupus.
• 00:42Lupus itself mimics, in some ways, a viral infection.
• 00:47The signals that we see in these patients are elevated interferons
• 00:51and that's a molecule that is important for fighting off viruses,
• 00:57and that's why lupus patients, they may say they have chronic fatigue.
• 01:01They feel terrible.
• 01:02Well they quite literally are feeling the effects of a viral infection
• 01:06because at the molecular level there are considerable similarities.
• 01:11One of the major things that we study
• 01:13is something called retroelements.
• 01:16So these have integrated into our genome over many millions of years
• 01:21and they comprise actually about 50% of our genome.
• 01:24Normally these elements are epigenetically silent.
• 01:28So you don't really see them in normal tissues.
• 01:30But in the setting of autoimmunity, they do become transcriptional active.
• 01:34We believe the body is recognizing some of these retroelements
• 01:38in a capacity that it thinks it's a virus.
• 01:47We do use cutting edge technologies like
• 01:50single cell RNA sequencing, spatial single cell RNA sequencing,
• 01:54and that's really able to kind of map the disease architecture at the cellular level.
• 02:00So you're able to get very high resolution information from that.
• 02:03Additionally, we take samples from patients
• 02:06and we move that into an in vitro setting
• 02:09and we're able to deliver specific controlled interventions
• 02:12to try to discern like cause and effect molecular mechanisms,
• 02:16and additionally we do use genetically engineered models
• 02:19that recapitulate certain aspects of human disease
• 02:22and, again, in that more controlled environment
• 02:25we’re able to test specific interventions and see their effect.
• 02:35Ultimately, one of the major goals is to
• 02:38better understand the source of both the innate
• 02:41and adaptive immune signals that manifest as autoimmunity in lupus patients.
• 02:46If we're able to better target things upstream and prevent
• 02:50that process from happening, perhaps we're better able to get
• 02:54precise, targeted therapies that have less side effects for patients.