Study Overturns Assumptions About Ptpn22 Risk Gene’s Role In Interferon Production

A new paper from nan University of Kansas overturns nan thought that a "risk gene" carried by millions of group worldwide influences accumulation of Type 1 interferon, a workhorse of nan immune system.

Humans pinch nan PTPN22 R620W familial consequence version person a higher chance of processing autoimmune diseases specified arsenic lupus aliases Type 1 diabetes.

"About 15% of North Americans of European ancestry person a mutation successful this cistron that puts them astatine higher consequence for autoimmune diseases," said Robin Orozco, adjunct professor of molecular biosciences astatine KU. "The cistron is associated pinch almost each autoimmune disease."

Researchers person agelong sought to understand why, particularly because nan aforesaid consequence cistron seems to connection protection against immoderate different diseases.

"With quality studies and rodent models, we recovered that group aliases mice pinch this mutation are amended capable to conflict disconnected cancers arsenic good arsenic viral infections," Orozco said. "We started to look astatine type 1 interferons because they are nan cardinal antiviral response."

Type 1 interferons are described arsenic "workhorses" of nan immune system. A long-standing presumption - based connected earlier rodent and compartment studies - was that nan PTPN22 mutation (called PEP successful mice) influences interferon production.

"Over a decade ago, studies suggested that PTPN22 controls type 1 interferon production, and we wanted to travel up connected that work," Orozco said.

The KU squad utilized rodent models engineered pinch CRISPR-Cas9 to transportation nan PTPN22/PEP variant, comparing them pinch mice successful which nan cistron was knocked retired and pinch regular mice.

"Our first research aimed to beryllium to ourselves that we could recapitulate nan published data," Orozco said. "The very first research successful my laboratory was conducted by an undergraduate student, Jenna Barnes, who is now successful an M.D.-Ph.D. programme astatine Cincinnati Children's Hospital. She tested whether this cistron really affects interferon production, and it didn't."

Initially, nan squad thought a laboratory correction mightiness person caused nan result.

"We repeated nan experiments aggregate times, pinch respective people, and consistently recovered that nan erstwhile results could not beryllium replicated," Orozco said.

The KU squad past cautiously examined nan earlier study to find why their results differed.

"We discovered that nan rodent exemplary utilized successful nan original study was not genetically clean," Orozco said. "The mice had further mutations beyond nan cistron being studied. Using a cleaner CRISPR-Cas9–generated rodent model, we showed that nan expected effect connected interferon accumulation didn't exist. Our activity recapitulated nan aged results utilizing nan original mice but revealed nary quality pinch our improved model."

While knocking retired PTPN22/PEP did not alteration interferon production, it did impact different cytokines associated pinch nan immune system. Orozco said that while PTPN22/PEP successful myeloid cells doesn't modulate type 1 interferons, it whitethorn play a domiciled successful different important immune signaling.

"The constituent of this insubstantial is to explain what PTPN22 is really doing successful immune cells, which is basal for knowing illness and imaginable treatments," Orozco said. "The findings correct nan erstwhile presumption that this cistron regulates type 1 interferon production. Our activity changes really researchers mightiness deliberation astir PTPN22 successful nan discourse of viral infections, crab and autoimmunity."

PTPN22/PEP's power connected nan immune strategy is important capable that aesculapian researchers could research compounds that interact pinch nan gene. Orozco's laboratory will thief laic nan groundwork for those efforts.

"For supplier discovery, we now person a clearer knowing of nan cistron earlier attempting to target it pinch mini molecules," Orozco said. "We're collaborating pinch Johns Hopkins and Purdue University to research a small-molecule inhibitor for PTPN22, pinch nan extremity of boosting immune responses against cancers specified arsenic melanoma and colorectal cancer. In our rodent model, knocking retired nan cistron did not origin broadside effects successful healthy, autoimmune-resistant mice, though it accelerates autoimmunity successful genetically susceptible mice."

The danasiwa was published successful nan diary ImmunoHorizons. Orozco and lead writer Barnes were joined by postgraduate students Anam Fatima Shaikh, Alec Bevis and investigation technician Tammy Cockerham. The activity was supported by nan K-INBRE program, nan Chemical Biology of Infectious Disease (CBID) Center of Biomedical Research Excellence (COBRE), nan KU Medical Center Jewell Summer Scholars program, nan Chemical Biology Training assistance program, nan KU Department of Molecular Biosciences and Office of Research, and nan Undergraduate Research Awards programme astatine KU.