24 July 2020 – Kids and Covid – (Coronavirus – China Virus – SarsCov2) may develop PIMS (pediatric inflammatory multisystemic syndrome) – update added – enzyme found

 

First COVID-19, then Kawasaki-like Disease in Children

July 24, 2020

Children with COVID-19 can develop pediatric, inflammatory multisystemic syndrome, or PIMS, which can lead to symptoms similar to that of a painful vasculitis condition called Kawasaki disease. Today we talk with Jagadeesh Bayry, Ph.D., and Caroline Galeotti, M.D., of the University of Paris who recently described in Nature Reviews Rheumatology related pediatric cases they saw in their clinic.

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In this week’s news roundup from Rheumatology Network, we begin by highlighting two reports on osteoporosis.

In one, doctors reporting in JAMA say that osteoporosis screening may be necessary for younger postmenopausal womenWe published a Q&A with Dr. Carolyn Crandall of UCLA who discusses the need to conduct osteoporosis screening in this population.

And, we featured a discussion with Dr. Suzanne Jan de Beur of Johns Hopkins University who explains that managing vitamin D levels may not be as straightforward as it would seemThere are factors that should be considered that are not often communicated to patients. We’ve posed an audio version of our discussion with Dr. Jan de Beur on rheumatologynetwork.com

And, this week we highlight two reports on COVID-19. In one, researchers writing in the Annals of the Rheumatic Diseases report that high doses of methylprednisolone with tocilizumab if needed, successfully resolved COVID-19 associated cytokine storm syndrome in most treated patients. You can learn more about those findings on rheumatologynetwork.com.

In today’s one-on-one interview, we feature a discussion with Jagadeesh Bayry, Ph.D., and Caroline Galeotti, M.D., of the University of Paris who recently described in Nature Reviews Rheumatology, pediatric cases of COVID-19 that were associated with the development of pediatric inflammatory multisystemic syndrome, or, PIMS in children. Children who developed PIMS exhibited signs of the vasculitis syndrome Kawasaki disease without having the disease itself. The condition eventually resolved in most of their patients. And, while the pandemic is under control in Paris, cases are still rising in most U.S. cities that may begin to see vasculitis symptoms in children described in this report.

“The current COVID-19 pandemic has given rise to many surprises, including the appearance of PIMS, with clinical and biochemical features distinct from that of classical Kawasaki disease and affecting children up to 17 years old. Although only a small proportion of SARS-CoV-2-infected children subsequently develop symptoms of PIMS (or MIS-C), most of them require intense clinical management because of the severity of the disease. As fundamental aspects of PIMS remain largely unknown, future investigations will require close interaction among various disciplines including paediatrics, internal medicine, rheumatology, immunology, genetics, infectiology, cardiology and epidemiology.,” they wrote in the article.

Click on the video to learn to learn more about this COVID-19-related condition in children.

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REFERENCE

Caroline Galeotti & Jagadeesh Bayry. “Autoimmune and inflammatory diseases following COVID-19,” Nature Reviews Rheumatology. News & Views | 04 June 2020.

from -https://www.rheumatologynetwork.com/view/osteoporosis-screening-may-be-necessary-for-younger-postmenopausal-women

Little Understood Enzyme May Point to Treatment for Kawasaki-Like Inflammatory Disease

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Blood vessel inflammation, illustration
Inside a blood vessel during inflammation. Computer illustration showing increased numbers of white blood cells in the blood vessel of a patient with inflammation.

The ADA2 gene provides instructions for making an enzyme called adenosine deaminase 2. ADA2’s function has been poorly understood. Previous studies suggest that the enzyme acts as a growth factor. The enzyme also appears to be involved in the growth and development of certain immune system cells including macrophages, which are a type of white blood cell that plays a critical role in inflammation. Now researchers at the La Jolla Institute for Immunology (LJI) report that ADA2 inhibits inflammation in blood vessels. Their findings offer a potential pathway to treating DADA2, an inflammatory blood vessel disease in children that is similar to Kawasaki disease.

Their study, “Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response,” is published in Science Advances and led by Sonia Sharma, PhD, associate professor at LJI.

“This is all pretty uncharted because for a long time, this was a very misunderstood enzyme,” explained Sharma. “But we showed that the metabolic activity of this enzyme, ADA2, is very important for restraining the immune system in both vascular cells and immune cells.”

Sharma’s lab is dedicated to uncovering the earliest cellular and molecular origins of inflammation. Her work has led her to focus on stromal cells. “We think the stromal cells’ capacity for sensing early pathogenic threats is likely very important for initially coordinating and developing the magnitude, duration, and quality of the downstream immune response,” said Sharma, “and ultimately determining whether the immune response is protective or pathogenic in nature.”

The researchers observed a group of uncharacterized human disease genes linked to lupus-like autoimmune diseases that all cause multi-organ systemic inflammation or vasculitis. For the new study, the researchers asked if any of the disease-linked genes play a role in how stromal cells respond to threats by initiating an innate immune response.

Their search led them to the enzyme ADA2. “For a long time, ADA2 was ignored—no one thought it did anything,” said Sharma. “What we know now is that both ADA1 and ADA2 play a much more nuanced role in regulating the bio-activity of purine nucleosides, which are powerful signaling molecules for the immune system.”

The researchers showed that ADA2 enzyme activity naturally inhibits the innate immune response by restraining the production of a cytokine called type 1 interferon beta. Although type 1 interferon beta is a protective molecule against viral infections and cancer, overexpression of type 1 interferon beta causes harmful inflammation.

“Mechanisms linking immune sensing of DNA danger signals in the extracellular environment to innate pathways in the cytosol are poorly understood. Here, we identify a previously unidentified immune-metabolic axis by which cells respond to purine nucleosides and trigger a type I interferon-β (IFN-β) response. We find that depletion of ADA2, an ectoenzyme that catabolizes extracellular dAdo to dIno, or supplementation of dAdo or dIno stimulates IFN-β. Under conditions of reduced ADA2 enzyme activity, dAdo is transported into cells and undergoes catabolysis by the cytosolic isoenzyme ADA1, driving intracellular accumulation of dIno,” explained the researchers.

“Loss of ADA2 drives metabolic dysregulation which in turn drives immune dysregulation and inflammation, so what we ended up identifying was new immuno-metabolic axis,” stated Sharma.

A better understanding of ADA2 and purine nucleoside metabolism may lead to new therapies for treating DADA2—a recessive genetic condition, where mutations in the CECR1 gene prevent it from correctly encoding ADA2—and other types of multi-organ systemic inflammation. Sharma believes that targeting the roots of these diseases will likely require a gene therapy approach or bone marrow transplants to reconstitute ADA2 in patients who cannot make the enzyme themselves.

“dIno is a functional immunometabolite that interferes with the cellular methionine cycle by inhibiting SAM synthetase activity. Inhibition of SAM-dependent transmethylation drives epigenomic hypomethylation and overexpression of immune-stimulatory endogenous retroviral elements that engage cytosolic dsRNA sensors and induce IFN-β. We uncovered a previously unknown cellular signaling pathway that responds to extracellular DNA–derived metabolites, coupling nucleoside catabolism by adenosine deaminases to cellular IFN-β production,” noted the researchers.

“I think our study suggests the simplest treatment must be pursued to correct the metabolic dysregulation—we must reconstitute this particular enzyme activity in patients, ultimately,” Sharma stated.

Sharma’s team plans to study ADA2 function in human cells and develop in vivo models of ADA2 deficiency. Sharma sees a connection between ADA2 research and COVID-19 studies.

“We’re studying COVID patients now to see if ADA2 activity or purine nucleosides change,” explained Sharma. The team is studying how the novel coronavirus may infect stromal endothelial cells and other cells involved in stimulating the body’s innate immune response.

They are also hoping to discover how the viral pathogenesis is connected to vascular complications and Multisystem Inflammatory Syndrome in Children (MIS-C), which has similarities to Kawasaki disease and DADA2.

 

from -https://www.clinicalomics.com/topics/patient-care/inflammatory-diseases/little-understood-enzyme-may-point-to-treatment-for-kawasaki-like-inflammatory-disease/

Published by txlady7061

We are more than just ourselves. We carry the DNA and the history of generations that came before. I’m a mom and a daughter. I’m a refugee. My mother is the only child that survived WWII in her family. She and my grandmother were the only ones left. My fathers family were forced to disown him, in writing, when we left Ukraine (former USSR.) They were going to shoot for California. They got as far and NY. I grew up in Queens. I left for the ARMY at the ripe old age of 23. Spent some time in VA and then on to TX. I live in TX. I am married to a wonderful man. I have a few kids. I AM JEWISH. I AM VERY CONSERVATIVE in my politics. I have a job that I go to EVERY DAY – 8-5, 5 days a week. My Hebrew name is Judith. Yihoodit. Baruch Hashem!

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