This installment is the last of the Marijuana/Hemp CBD series of columns and focuses on the mechanism through which CBD (Cannabidiol Hemp Oil, remember?) works to cure or reduce the magnitude of various ailments.

The ailments that CBD seems to help are arthritis, chronic pain, heart and lung malfunctioning coordinating with the central nervous system. Furthermore, although much more research is needed, it is tentatively concluded that CBD would help reduce autoimmune and inflammatory responses that trigger HIV, cancer and sclerosis.

In terms of dermatological field, CBD is effective in three powerful areas: acne breakouts and redness, preventing excessive oil production and aging over time. Concerning ailments in other animals, such as dogs, cats, horses and birds, we are unaware that their ailments can be reduced or cured by CBD for certain. I have not encountered authoritative literatures on CBD being used to treat animals. However, that is due to my lack of proper literature search. I am convinced there are some solid research literatures available in the field, especially from the research facilities and universities of Israel.

Now we move onto the most important subject of "Why and what does CBD do to cure all that ailments?" Readers, if you are educated through a science class at a college level, you can at least feel that a plant derived chemical would cure or reduce so many wide varieties of ailments as mentioned above can't be real. There has to be some either mistake, misjudgment or worse, a salesman's super hype. Yes, that would be a natural instinct if you had gotten a proper science education in your youth. (Maybe though, you might have slept through it, ha!) So, did I. I said to myself that a chemical extracted from the plant called Hemp, which is available basically everywhere in the world if you look hard, would be so widely effective in treating diseases that seem so remotely connected to each other.

So, I gave myself a mission to dig into this myth. I wanted to find out any credible scientific papers that focus on that question, and that question alone. So, I have gotten some 20 papers of various titles and subjects on CBD. My journey was to find out the very question of why CBD could be so effective for so wide a variety of ailments. My reading these papers started a week ago, and I was nearing the end with no clear conclusion. To read 20 papers in one week is a task I do not want to do again. Finally, I reached the last one, yes, 20th, when my brain got a shot of adrenalin and literally woke up from just a bureaucratic reading to sharply focused excitement. The article title is "Can CBD Really Do All That?" by Moises Velasquez-Manoff, and this paper appeared in New York Time. Due to the limited space and time, I have summarized his description of CBD effect on human body in brief statements.

First, primitive living creatures such as prehistoric fish started to migrate out of the ocean about 460 million years ago. Living on the land gave many advantages to small living creatures than the size-ranked ocean living. One could see farther, and there is less fear of becoming larger foes' lunch. The primitive small living creatures began their journey of evolution to adopt their ability to fit the environment. Today we humans rank as the top dweller of that vast pyramid.

Secondly, in the meanwhile, hemp appeared on the land about 38 million years ago. What hemp brought out into the animal kingdom, including us humans, was a a very effective weapon in immunology. Simply put, hemp produces CBD, which, upon entering human body, produces a material named CB1 Receptor and CB2 Receptors. C 1 ends up in brain, kidney, lungs and liver, while CB2 Receptor ends up in white blood cells of immune system, the gut and the spleen. See Fig 344-1. Without going through a complex and specialized scientific statement, my understanding is that these receptors would then manipulate and guide the human immunological system to better health. As you can see, CB 1 and CB2 combined would cover all the sickness and chronic pain ailments described above. -I would still say that I am amazed that a plant, now called hemp, which showed up on the dry land on the earth 422 million years later than the first primitive animal moved from the ocean to the dry land would know how to fight diseases in the human body and brought forth the very chemical and physiological weapon to do it. Is it just a spectacular coincidence, or God's will and creation?

Nevertheless, we do have this potent weapon called hemp, the most powerful and widely applicable-to-diseases plant on the earth. The plant has been, however, badly mistreated by this nation. In 1937, marijuana was banned nationwide by our country. It does smell of racial prejudice against Mexicans who were entering through the border at that time. I feel that the history may be repeating now. However, I strongly feel that we Americans should positively open up the aggressive research projects on what CBD does for the human health NOW. Israel has been at it, and I am assuming their results would be good. Why are we standing idol and watching the world go by? Hemp produces CBD, which is very widely applicable to many human ailments, and CBD is proven to be positively efficacious with little negative side effects. Let's fund our own research. We have nothing to lose, only much to gain.

This Companion to Aging column appears each week in the Seacoast Sunday features section. You can read earlier installments at http://www.seacoastonline.com. Please send your thoughts about aging to Sasano@umelink.com, Sam Asano, P.O. Box 26, New Castle, NH 03854 or (cell) 781-389-2356 or email Sam at sasano@umelink.com.

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Companion to Aging: The U.S. should fund CBD research - Foster's Daily Democrat

Researchers at the La Jolla Institute for Immunology (LJI), have found definitive evidence that CD4 T cells are not to blame when a mild dengue viral infection morphs into a severe and sometimes deadly dengue hemorrhagic fever/dengue shock syndrome.

This finding is important to both the basic understanding of this disease--the world's most common mosquito-borne illness--and to the hunt for an effective vaccine for dengue.

"We found no evidence to support the common dogma that these T cells are responsible for turning a mild infection to a severe one. This will help us narrow the search for the true culprit," says the study's lead investigator Yuan Tian, Ph.D., an AAI Intersect Fellow, and a Bioinformatics Student at LJI, in the December 24, 2019, issue of Cell Reports.

The goal of the LJI study was to define the molecular pattern of dengue-specific CD4 T cells and to investigate whether there is a difference in the T cell response between patients with mild dengue fever or with severe dengue hemorrhagic fever.

When analyzing dengue-specific CD4 T cells, the researchers realized that the responding CD4 T cells have both a pro-inflammatory function and an anti-inflammatory function which is typically not seen in acute viral infections.

To comprehensively define these dengue-virus specific T cells in hospitalized patients, researchers used whole transcriptome analysis to determine if there was a difference in the quality of the increased response.

This approach allows identifying all RNA transcripts--produced when a gene's DNA sequence is copied, or transcribed--within the transcriptome of dengue-specific CD4 T cells in hospitalized patients being treated for either mild or for severe dengue infection.

These patients were being treated in Sri Lanka, where dengue fever is endemic.

"This is a very powerful approach to detect gene expression activity because all genes upregulated in response to the virus can be identified. It is completely unbiased and does not rely on pre-selected genes," says the study's senior investigator, Daniela Weiskopf, Ph.D., an instructor at LJI, in a related press release.

The research team, to their surprise, detected no difference in the genomic profile of dengue-virus specific CD4 T cells regardless if they isolated them from patients with mild or severe dengue infection.

"The CD4 T cell response in the severe disease does not look different so that cannot be the switch we are all looking for," Tian says.

"In fact, based on some intriguing preliminary findings, we speculate that to counteract the severe immune response occurring in acute cases, these dengue-specific CD4 cells may have gradually acquired the ability to produce more IL-10 by converting IFN. It is as if they are trying to calm themselves, calm the inflammation.

The double-positive CD4 T cells could actually be helping, rather than hurting."

Dr. Tian concluded saying that he hopes these findings will serve to "help guide efforts to develop effective dengue vaccines by improving our understanding of this novel T cell response.

This work was performed as a project of the Human Immunology Project Consortium (HIPC) and supported by the National Institute of Allergy and Infectious Diseases grants U19 AI118626 and P01 AI106695 and NIH contracts HHSN272200900042C and HHSN27220140045C. It was also supported Shared Instrumentation Grants S10 RR027366, S10 OD018499, and S10 OD016262, from the National Institutes of Health.

No conflicts of interest were disclosed.

The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases.

Dengue News is published by Precision Vaccinations

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Dengues Progression to a Severe Case Found Not Related to T Cells - PrecisionVaccinations

National Institute of Immunology, an Autonomous Research Institute, Aruna Asaf AliMarg, New Delhi-110067, has invited applications for admission to Ph.D. Programme for the Academic Year 2020-21.

Research at NII encompasses board interdisciplinary areas of Immunology, Infectious and Chronic Disease Biology, Molecular and Cellular Biology and Chemical, Structural and Computational Biology.

Eligibility: Applicants should hold an M.Sc. in any branch of Science, M.Tech., MBBS., M.V.Sc., M.Pharm. or equivalent qualifications as per norms of the Jawaharlal Nehru University (JNU), New Delhi.

Applicant should have at least 60% aggregate score or equivalent grade in Senior Secondary Certificate (10+2) and Bachelor's degree, and 55% aggregate score or equivalent grade in Master's degree in case of General category. Five percent relaxation in aggregate scores in Senior Secondary, Bachelor's and Master's degrees will be applicable for the candidates from reserved categories [OBC (NCL), SC/ST and PwD].

Those who have completed or are likely to complete the required courses in the current academic year can also apply.

Selection to the Ph.D. programme will be through two channels: One will be the Computer based Entrance Examination, NII-2020, to be conducted by NII at multiple centres all over India on 23rd February 2020 (Sunday) and the other will be through the Joint Graduate Entrance Examination in Biology and Interdisciplinary Life Sciences (JGEEBILS-2020).

An applicant must qualify at least one of these two examinations. They will be short-listed for an interview based on either NII Entrance examination or JGEEBILS 2020 marks.

Selected candidates will be enrolled in the Ph.D programme affiliated with Jawaharlal Nehru University, New Delhi.

The online application will be available from December 20, 2019 onwards. The last date for submission of applications is January 31, 2020. Candidates applying through JGEEBILS-2020 must also submit an application through NIl application portal, along with application fees and the JGEEBILS-2020 admit card.

Detailed information, including online application procedure and other information are available at http://www.nii.res.in. Women candidates are encouraged to apply

For more details, visit http://www.nii.res.in

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Research at National Institute of Immunology: Apply by January 31 - Mathrubhumi English

BROOKLINE, Mass., Dec. 24, 2019 /PRNewswire/ --Chester Allan Alper, MD is recognized by Continental Who's Who in the field of Medicine as a Top Doctor for the successes he has accrued as a Pediatrician, Genomist, & Immunologist at Boston Children's Hospital.

Recognized as one of the most ubiquitous medical facilities in the United States, Boston Children's Hospital prides itself on its exceptional customer service and hands on approach in assuring the health and wellness of their patients. With communication, respect, excellence, accountability, teamwork and innovation at the forefront of the company's values, Boston Children's Hospital is a well-regarded medical practice whose mission is to be the "leading source of research and discovery." Devoted to implementing quality and efficient patient safety in everything they do for over 140 years, the medical institution hopes to advance pediatric care worldwide.

Leading an impressive career for more than fifty-six years, Dr. Alper is venerated by his patients and peers for his outstanding contributions to the medical profession. With participation in groundbreaking medical research in genomics and immunology, he has conducted research in establishing population markers for Type One Diabetes in children. He attributes his success to working with good people, and a matter of chance. When asked his advice to novices in the industry, he states, "Persevere and maintain curiosity, critical thinking and open-mindedness."

Well versed in the areas of Genomics and Immunology Research, Dr. Alper has studied the genetics of complex (polygenic) disease in humans. He and his colleagues have investigated expansively the relationship between genetic differences in the human MHC with differences in the immune function of a variety of "white blood cells," or leukocytes.

An academic scholar, Dr. Alper attained his Medical Degree from Harvard Medical School. Thereafter, he went on to complete both his internship and residency at Boston City Hospital. Curiosity has driven him ever since. Upon entering his fellowship in Hematology, Dr. Alper moved into pediatrics, immunology and, finally, genetics. This led to discoveries in the field of the serum proteins. Once it was clear that several of these were encoded within the major histocompatibility complex, his interest and focus shifted to the genetics of human autoimmune diseases, including type 1 or childhood diabetes.

A pillar in the medical community, Dr. Alper has co-authored numerous peer-reviewed reports such as " A New Pedigree-Based SNP Haplotype Method for Genomic Polymorphism and Genetic Studies" and "A stochastic epigenetic Mendelian oligogenic disease model for type 1 diabetes".

In his spare time, Dr. Alper plays the recorder, and does Chinese calligraphy and cartooning.

Dr. Alper dedicates this recognition to his current colleague Instructor Charles Larsen.

For more information, please visit http://www.childrenshospital.org

Contact: Katherine Green, 516-825-5634 pr@continentalwhoswho.com

SOURCE Continental Who's Who

http://www.continentalwhoswho.com

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Chester Allan Alper, MD is recognized by Continental Who's Who - PRNewswire

New finding takes understanding on how babies are protected against infections such as chickenpox to a different level

Women who been infected by chickenpox may transmit the DNA of the disease-causing virus to their babiesduring pregnancy, stimulatingtheirimmunity against the infection and protecting them, a study found.

This mother-to-child transfer of viral DNA may be responsible for long-lasting protection against chickenpox infection seen during childhood, researchers from National Institute of Immunology and St Stephens Hospital, Delhi, said. Their study was published in journal Viral Immunology.

The new finding takes the understanding on how babies are protected against infections such as chickenpox to a new level.

Currently, it isunderstood that mothers provide babies protection against a variety of common infections by transferring readymade antibodies to them. The protection lasts for 12-15 months; if a baby catches an infection during this period, it gets ill in a mild form and develops its own long-lasting immunity for that disease.

The new study led by Jacob Puliyel from St Stephens Hospital showed that it was, however, different in the case of chickenpox. Scientists found that mothers developedsubclinical viremia and the viral DNA was transferred to their babies. The study was done in 350 mothers and their newborn babies.

The babies of mothers, who had chickenpox earlier in their life, develop a long-lasting active immunity with the transfer of chickenpox DNA from mothers, instead of the short-term passive protection provided by the transfer of readymade antibodies. It is likely that the antibodies are developed actively in the foetus, researchers said.

Several studies have already shown that chickenpox can get reactivated due to stress following surgeries and space travel. But, subclinical reactivation of chickenpox, induced by the stress of pregnancy, is being reported for the first time, they added.

Further, they said the chickenpox parties held in countries like in the United Kingdom to get childrenexposed to others with chickenpoxwas not necessarily a bad idea. They got naturally infected in childhood, when the disease was typically mild, and later in life they were likely to pass on protectingchickenpox antibodies and DNA to their offspring.

The new findings make a case for review of vaccination policies for chickenpox, the authors said.

Besides Puliyel, the team consisted of Alaknanda Mishra, Ashwani Kesarwani, K Varsha Mohan and Pramod Upadhyay of National Institute of Immunology and Vivek Ranjan and Sandeep Narayan Lal of St Stephens Hospital. (India Science Wire)

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Study finds mechanism for mother-child transmission of immunity to chickenpox - Down To Earth Magazine

Omalizumab may significantly improve lung function in adolescents with moderate to severe uncontrolled asthma, according to study results published in the Annals of Allergy, Asthma, and Immunology.

Omalizumab is a humanized monoclonal antibody against immunoglobulin E that was approved for the treatment of asthma in 2013 and has demonstrated significant improvement in lung function in adolescents in real-world studies. However, the effect of omalizumab on the lung function of adolescent patients in placebo-controlled trials has not been established. Therefore, researchers assessed the effect of omalizumab on lung function and eosinophil counts in adolescents aged 12 to 17 years with uncontrolled moderate to severe allergic asthma using a post-hoc analysis of 8 randomized trials. Of 340 adolescents, 203 received omalizumab and 137 received placebo.

Omalizumab increased all baseline lung function variables more than placebo by the end of the study (3.0% [P =.035], 120.9 mL [P =.009], and 101.5 mL [P =.033] for percent predicted forced expiratory volume in 1 second [FEV1], absolute FEV1, and forced vital capacity, respectively). In addition, the least squares mean difference demonstrated a greater reduction in eosinophil counts with omalizumab compared with placebo (P =.001).

The significant improvements in lung function observed in patients receiving omalizumab emphasize the potential effect of omalizumab in patients who remain uncontrolled on current therapies and the need to optimize treatment early in the disease course, the researchers concluded.

Disclosure: This clinical trial was supported by Genentech, Inc., a member of the Roche Group and Novartis Pharma AG. Please see the original reference for a full list of authors disclosures.

Reference

Busse WW, Humbert M, Haselkorn T, et al. Effect of omalizumab on lung function and eosinophil levels in adolescents with moderate-to-severe allergic asthma [published online November 21, 2019]. Ann Allergy Asthma Immunol. doi:10.1016/j.anai.2019.11.016

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Omalizumab Improves Lung Function in Adolescents With Uncontrolled Asthma - Pulmonology Advisor

A Migliore,1 G Gigliucci,1 RJ Petrella,2 RR Bannuru,3 X Chevalier,4 E Maheu,5 R Raman,6 G Herrero-Beaumont,7 N Isailovic,8 M Matucci Cerinc9

1Rheumatology Unit, San Pietro Fatebenefratelli Hospital, Rome, Italy; 2Department of Family Medicine, School of Kinesiology Western University, Western Centre for Public Health & Family, London, Ontario, Canada; 3Center for Treatment Comparison and Integrative Analysis Division of Rheumatology, Tufts Medical Center, Boston, MA, USA; 4Department of Rheumatology, Hpital Henri Mondor, Creteil, France; 5Rheumatology Department, AP-HP, Saint-Antoine Hospital, Paris, France; 6Academic Department of Orthopaedics, Hull and East Yorkshire NHS Trust, Castle Hill Hospital, Cottingham, UK; 7Joint and Bone Research Unit, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain; 8Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milan, Italy; 9Division of Rheumatology AOUC, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

Correspondence: N IsailovicDivision of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Via A. Manzoni 56, Rozzano 20089, Milan, ItalyTel +39-02-8224-5118Email natasa.isailovic@humanitasresearch.it

Abstract: Osteoarthritis (OA) is a rheumatic disease that affects the well-being of the patient, compromises physical and mental function, and affects other quality of life aspects. In the literature, several evidence-based guidelines and recommendations for the management of knee osteoarthritis (KOA) are available. These recommendations list the different therapeutic options rather than addressing a hierarchy between the treatments and defining the real target. Therefore, a question arises: are patients and physicians satisfied with the current management of KOA? Actually, the answer may be negative, thus suggesting a change in our therapeutic strategies. In this article, we address this challenge by suggesting that it is time to develop a treat to target strategy for KOA.

Keywords: osteoarthritis, knee osteoarthritis, treat to target

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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CAMBRIDGE, Mass.--(BUSINESS WIRE)--Rheos Medicines (Rheos), a biopharmaceutical company harnessing insights in immunometabolism to create a new class of therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer, today announced that it has entered into a worldwide exclusive collaboration, option and license agreement with Roche to discover, develop and commercialize novel therapeutics in the field of immunometabolism.

We are thrilled to be leveraging our expertise in human immune cell metabolism in partnership with Roche, said Barbara Fox, Chief Executive Officer of Rheos. We believe that our teams deep experience in immunology and cellular metabolism along with our unique approach have the potential to unlock a new frontier in precision medicine for immune mediated disease. This partnership will help to accelerate the translation of insights in immunometabolism to the development of groundbreaking therapeutics for patients with autoimmune and inflammatory diseases.

"We are excited to partner with Rheos and look forward to the development of a novel class of therapeutics for patients with autoimmune and inflammatory disease, said Gijs van den Brink, SVP and Global Head of Immunology, Infectious Diseases and Ophthalmology at Roche Pharma Early Research and Development. "We believe Rheos' proprietary platform and expertise in immunometabolism is a strong complement to Roche's expertise in autoimmunity and inflammation and in developing and commercializing innovative therapies."

Under the terms of the agreement, Rheos will conduct an exclusive research effort to identify novel targets in immunometabolism that modify the fate or function of certain human immune cells. In addition, Rheos will also be responsible for drug discovery efforts under the collaboration. Roche will receive an option to exclusively license a defined number of programs emerging from the collaboration. For certain products within the collaboration, Rheos and Roche could share worldwide development and US commercial rights.

Rheos will receive an upfront cash payment of $42.5 million upon execution and will be eligible to receive up to approximately $90 million for specified research and preclinical development milestones as well as option fees. Rheos will also be eligible to receive up to an additional approximately $660 million in specified development, regulatory and sales related milestones across the programs and tiered royalties on net sales. For those products for which Rheos and Roche could share development and commercial rights Rheos will be entitled to additional financial compensation within the US and ex- US commensurate with the share of its financial investment in development and commercialization.

About Rheos Medicines

Rheos Medicines is a biopharmaceutical company harnessing insights in immunometabolism to develop novel therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer. Our approach targets the underlying intracellular metabolism of immune cells and has the potential to unlock a new frontier in drug discovery for immune-mediated disease. Through a proprietary platform and product engine that integrates multiple omic datasets, we systematically define the biologic links between immune cell metabolism and function and simultaneously identify new drug targets and biomarkers of disease to bring precision to the treatment of immune-mediated diseases. We have assembled leading scientists whose discoveries opened the field of immunometabolism, clinicians with a deep understanding of immune-mediated diseases, and an experienced biotech leadership team. Rheos was founded by Third Rock Ventures and is located in Cambridge, MA. For more information, please visit http://www.rheosrx.com.

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Rheos Medicines Announces Worldwide Collaboration with Roche to Discover and Develop Novel Medicines in the Field of Immunometabolism - Business Wire

PROFESSOR Ron Penny, the man who diagnosed the first case of AIDS in Australia in 1982 and a leading researcher in the field, died overnight.

Penny and his family arrived in Australia in 1938 after fleeing the Nazis in Poland.It was that family history that defined in his career.

After diagnosing a gay man of having AIDS, he fought hard against the discrimination that followed in Australia.

The political issue was not AIDS itself; it was the discrimination and the repercussions of the way the straight community thought about gay men, Penny told The Sydney Morning Herald in the early 2000s.

The attitude was they caused it themselves, it is due to their lifestyle, and I saw that as a very dangerous process.

Being Jewish I think I understand discrimination my family left Poland because of the antisemitism and I could see that it was just the same story with different names.

Ron Penny (left), pictured with United Nations Special Commission chair Richard Butler.

Penny, who was St Vincents Hospitals Centre for Immunology inaugural director and went on to become one of Australias most influential scientists, made it his mission to defend the human rights of individuals.

I was trying to kill all those stories that you can get it from touching the handrail on a public bus, you can get it from going to the hairdressers, from gay men breathing on you or shaking hands.

Penny was honoured by many in his field and the community as a pioneer.

Don Baxter, the former head of the Australian Federation of AIDS Organisations said Penny was a strong leader and more than just a doctor in the early days of the AIDS epidemic.

He knew when to take risks and be publicly critical of the [health] minister commonwealth or state and when not to he was very much an activist.

Former federal health minister Neal Blewett said Penny was one of the heroes of the early days of HIV.

He was quite self-effacing and quite modest and I perhaps didnt realise how valuable he was.

Ron Penny, third from right, at a NSW Jewish Board of Deputies function to honour the St Vincents hospital.

In 2008, while chair of the NSW Governments Chronic, Aged and Community Health Priority task force, and a member of the NSW Health Care Advisory Committee, Penny was appointed to the Federal Governments National Health and Hospital Reform Commission

In 1993 the Commonwealth recognised Penny with an Officer of the Order of Australia (AO) for his service to medical research and education, particularly in the field of clinical immunology.

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A hero of the early days of AIDS - The Australian Jewish News

For many years, the parents of children with autism have reported that behavioral symptoms diminished when the child had a fever. The fever phenomenon has been documented in at least two large-scale studies over the past 15 years, but the reasons behind it have continued to mystify scientists.

Now, a new study by researchers at Harvard Medical School and MIT sheds light on the cellular mechanisms that appear to underlie this phenomenon.

In a study of mice, published Dec. 18 inNature, the researchers found that in some cases mimicking bacterial infection, an immune molecule called IL-17a is released and suppresses a small region of the brains cortex linked to social behavioral deficits in animal models.

Our findings finger the signaling cascade that leads to temporary alleviation of autism-like symptoms upon exposure to inflammatory conditions, highlighting the complex interplay between the nervous and immune systems in neurodevelopmental disorders such as autism, said study co-corresponding authorJun Huh, assistant professor of immunology in the Blavatnik Institute at HMS.

People have seen this phenomenon before [in people with autism], but its the kind of story that is hard to believe, which I think stems from the fact that we did not know the mechanism, saidGloria Choi, the Samuel A. Goldblith Career Development Assistant Professor of Applied Biology and an assistant professor of brain and cognitive sciences at MIT. Now the field, including my lab, is trying hard to show how this worksall the way from the immune cells and molecules to receptors in the brainand how those interactions lead to behavioral changes.

Although findings in mice do not always translate into humans, the study may help guide the development of strategies that could help reduce some behavioral symptoms of autism or other neurologic disorders, said Choi, who is also a faculty member of MITs Picower Institute for Learning and Memory.

The lead authors of the research are MIT graduate student Michael Douglas Reed and MIT postdoctoral fellow Yeong Shin Yim.

Immune influence

Choi and Huh previously explored other links between inflammation and autism. In 2016,they showedthat mice born to mothers who experience severe infections during pregnancy are much more likely to show behavioral symptoms such as deficits in sociability, repetitive behaviors and abnormal communication. They found these symptoms stem from exposure to maternal IL-17a, which produces defects in a specific brain region of the developing embryo. The brain region, S1DZ, is part of the somatosensory cortex and believed to be responsible for sensing where the body is in space.

Immune activation in the mother leads to very particular cortical defects, and those defects are responsible for inducing abnormal behaviors in offspring, Choi said.

A link between infection during pregnancy and autism in the offspring has also been documented in humans. A 2010 study that included children born in Denmark between 1980 and 2005 found that severe viral infections during the first trimester of pregnancy led to a threefold increase in risk for autism, and serious bacterial infections during the second trimester were linked with a 1.42-fold increase in risk. These infections included influenza, viral gastroenteritis and severe urinary tract infections.

In the new study, Choi and Huh turned their attention to the often-reported link between fever and reduction of autism symptoms.

We wanted to ask whether we could use mouse models of neurodevelopmental disorders to recapitulate this phenomenon, Choi said. Once you see the phenomenon in animals, you can probe the mechanism.

The researchers began by studying mice that exhibited behavioral symptoms due to exposure to inflammation during gestation. They injected these mice with a bacterial component called LPS, which induces a fever response, and found that the animals social interactions were temporarily restored to normal.

Further experiments revealed that during inflammation these mice produce IL-17a, which binds to receptors in S1DZthe same brain region shown to be affected by maternal inflammation. The experiments showed that IL-17a reduces neural activity in S1DZ, making mice temporarily more interested in interacting with fellow mice.

When researchers inhibited IL-17a or knocked out the receptors for IL-17a, mice did not experience a reversal of symptoms, a finding that pinpointed IL-17a as the responsible trigger. The experiments also showed that simply raising mices body temperature did not have any effect on behavior, offering further evidence that IL-17a is, indeed, the critical player behind reversal of symptoms.

This suggests that the immune system uses molecules like IL-17a to directly talk to the brain, and it actually can work almost like a neuromodulator to bring about these behavioral changes, Choi said. Our study provides another example as to how the brain can be modulated by the immune system.

Whats remarkable about this paper is that it shows that this effect on behavior is not necessarily a result of fever but the result of cytokines being made, said Dan Littman, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology at New York University, who was not involved in the study. Theres a growing body of evidence that the central nervous system, in mammals at least, has evolved to be dependent to some degree on cytokine signaling at various times during development or postnatally.

Behavioral effects

The researchers then performed the same experiments in three additional mouse models of neurologic disorders. These mice lack a gene linked to autism and similar disorderseitherShank3,Cntnap2orFmr1. These mice all show deficits in social behavior similar to those of mice exposed to inflammation in the womb, even though the origin of their symptoms is different.

Injecting those mice with LPS did produce inflammation, but it did not have any effect on their behavior. The reason for that, the researchers found, is that in these mice, inflammation did not stimulate IL-17a production. However, if the researchers injected IL-17a into these mice, their behavioral symptoms did improve.

This suggests that mice who are exposed to inflammation during gestation end up with their immune systems somehow primed to more readily produce IL-17a upon exposure to other inflammatory conditions later in their life. Choi and Huh havepreviously shownthat the presence of certain bacteria in the gut can also prime IL-17a responses. They are now investigating whether the same gut-residing bacteria contribute to the LPS-induced reversal of social behavior symptoms that they found in the newNaturestudy.

Huh and Chois labs are also exploring whether any immune molecules other than IL-17a may affect the brain and behavior.

Whats fascinating about this communication is the immune system directly sends its messengers to the brain, where they work as if theyre brain molecules, to change how the circuits work and how the behaviors are shaped, Choi said.

It was amazing to discover that the same immune molecule, IL-17a, could have dramatically opposite effects depending on context: Promoting autism-like behaviors when it acts on the developing fetal brain and ameliorating autism-like behaviors when it modulates neural activity in the adult mouse brain, Huh said. This is the degree of complexity we are trying to make sense of.

The research was funded by the Jeongho Kim Neurodevelopmental Research Fund, Perry Ha, the Hock E. Tan and K. Lisa Yang Center for Autism Research, the Simons Center for the Social Brain, the Simons Foundation Autism Research Initiative, the Champions of the Brain Weedon Fellowship, and a National Science Foundation Graduate Research Fellowship.

Adapted from an MITnews release

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Cracking the Fever-Autism Mystery - Harvard Medical School