Translational Medicine Friday

Researcher Jonathan Kipnis --- A pioneer in Neuro-immunology

4/25/2025

Val's Note: Kipnis was formerly at the University of Virginia, now at the Washington University in St. Louis.

He is also an academic editor of the Journal of Experimental Medicine which publishes papers on immunology, cancer biology, vascular biology, microbial pathogenesis, neuroscience and stem cell biology.

Vaccinations & Neuro-Diversity --- The Need for a more Nuanced Approach

4/25/2025

Val's Take/Conjecture

If you ask Google AI about autism or ADHD, it's going to come back and say current research finds that Vaccinations do not "CAUSE" autism or ADHD.

I asked Google AI about vaccinations and NEUROIMMUNE Disorders, this is the result:

Vaccinations are generally safe and recommended for people with neuroimmune disorders, but timing and specific vaccine types should be considered.

Inactivated vaccines are considered safe, while live vaccines are generally avoided during immunotherapy.

Vaccinations must also be avoided during relapses or exacerbations of neuroimmune diseases.

In fact, medical professionals do have guidelines regarding vaccinations and people with Neuro-Immune Disorders such as Multiple Sclerosis.

The emerging neuroimmune hypothesis of bipolar disorder: An updated overview of neuroimmune and microglial findings (2024)

The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms (2025)

Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype (2025)

Psychiatric adverse events following COVID-19 vaccination: a population-based cohort study in Seoul, South Korea (2024)

"COVID-19 vaccination increased the risks of depression, anxiety, dissociative, stress-related, and somatoform disorders, and sleep disorders while reducing the risk of schizophrenia and bipolar disorder.

"Therefore, special cautions are necessary for administering additional COVID-19 vaccinations to populations vulnerable to psychiatric AEs (Adverse Events)."

"CAUSE"

When it comes to "CAUSE" and not only Neuro-Developmental & Psychiatric Disorders but also classic Neuro-Immune Disorders & Cancer ----
- There is often NOT 1 Cause --- they are "MULTI-FACTORAL"
- The Multitude of these FACTORS are driving the need for Individualized, Personalized Medicine.

ON THE OTHER HAND

People with Neuro-Developmental & Psychiatric Disorders, Classic Neuro-Immune Disorders and Cancer ----
- Are the very people who would be most at risk for the most serious outcomes of some of these diseases.

Understanding Neuro-Developmental & Psychiatric Disorders as Neuro-Immune Disorders

Neuroimmunity at the edge: The skull as a brain - periphery immunological hub in autism spectrum disorder (2025)

Evaluating the link between immune characteristics and attention deficit hyperactivity disorder through a bi-directional Mendelian randomization study (2024)

Conclusion: Studies indicate that the immune system’s response influences the emergence of ADHD.

The findings greatly improve our understanding of the interplay between immune responses and ADHD risk, aiding in the development of treatment strategies from an immunological perspective.

I just don't think it is that counter-intuitive that there might need to be some special considerations with regard to vaccines and Neuro-Immune Neuro-Developmental & Psychiatric Disorders.

We need to get out of the Anti-Vaxx/Conspiracy Theorist construction of this debate.

Recognizing legitimate issues and nuance supported by the evidence might help.

Maternal Immune ActivatioN, Gene Expression & the Immune System --- DNA & RNA Methylation

4/20/2025

"DNA methylation is the addition of a methyl group to the molecular structure of DNA, which then alters the gene expression."

DNA and RNA methylation directly linked for the first time (2025)

Val's Take/ Conjecture

I think "Lifestyle Choices" are important AND so are DNA Methylation Patterns established In Utero.
There is a certain amount of "FETAL PROGRAMMING" that seems to be going on that we feel highly uncomfortable acknowledging.
These are DEVELOPMENTAL DISORDERS --- if we are missing that --- we're missing the boat.

RNA m6A methylation in psychiatric disorders (2023)

Genetic evidence for causal effects of immune dysfunction in psychiatric disorders: where are we? (2024)

"Here we synthesize these new findings from genomics and genetic causal inference studies on the role of immune dysfunction in major psychiatric disorders and reconcile these new data with pre-omics findings.

"By reconciling these evidences, we aim to identify key gaps and propose directions for future studies in the field."

In Utero Exposures, Infant Growth, and DNA Methylation of Repetitive Elements and Developmentally Related Genes in Human Placenta (2011)

"DNA methylation patterns are essential for the growth and maintenance of tissue-specific expression profiles in different cell types during development, and these patterns become set during in utero development."

Circadian Rhythms Correlated in DNA Methylation and Gene Expression Identified in Human Blood and Implicated in Psychiatric Disorders (2024)

Towards a neurodevelopmental model of bipolar disorder: a critical review of trait- and state-related functional neuroimaging in adolescents and young adults (2025)

DNA and RNA methylation, initially thought to operate as distinct pathways, have been shown to interact closely, shifting our understanding of gene regulation. (2025)

Inhibition of aging-induced DNA hypermethylation by si-Dnmt3a/3b in pre-implantation embryos improves aberrant social behavior in offspring (2025)

"Our study indicates that male aging exert an influence not only on DNA methylation modification in sperm and pre-implantation embryo, but also on neurobehavioral abnormalities of their offspring.

"Repairing DNA methylation in pre-implantation embryos may offer a promising avenue for ameliorating abnormal social behavior in offspring."

The Genesis of Schizophrenia: An Origin Story (2024)

"Ultimately, rather than a focus on therapeutic intervention during adolescence or adulthood, principles of prediction and prophylaxis in the pre- and perinatal and neonatal stages may best comport with the biology of schizophrenia to address the early-stage perturbations that alter the normative neurodevelopmental trajectory."

Paternal immune activation in neuro-Developmental & Psychiatric Disorders

4/20/2025

Is paternal immune activation just as important as maternal immune activation?

Time to rethink the bi-parental immune priming of neurodevelopmental model of schizophrenia (2023)

Highlights

Paternal immune activation might enhance schizophrenia risk.

Epigenetic processes might mediate the effects of paternal immune activation.

Bi-parental immune priming seems to drive schizophrenia immunopathogenesis.

Depletion of the paternal gut microbiome alters sperm small RNAs and impacts offspring physiology and behavior in mice (2025)

"This study demonstrates that the gut-germline axis influences sperm small RNA profiles and offspring physiology, with specific impacts on offspring affective and/or coping behaviors.

"These findings may have broader implications for other animal species with comparable gut microbiota, intergenerational epigenetics and developmental biology, including humans."

Paternal immune activation by Poly I:C modulates sperm noncoding RNA profiles and causes transgenerational changes in offspring behavior (2024)

The missing half: Paternal immune activation's role in transgenerational sex differences (2024)

More Immune Connections to Neuro-Developmental & Psychiatric Disorders: Mast Cells

4/19/2025

"Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders."

Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines (2023)

Mast Cells in Autism Spectrum Disorder-The Enigma to Be Solved? (2024)

Identification of immune-related biomarkers in peripheral blood of schizophrenia using bioinformatic methods and machine learning algorithms (2023)

Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions (2024)

[This is an interesting article and what it is talking about among other things is that --- it is hard to work with these patients with compassion --- they burn clinicians out.

As more of a MULTI-SYSTEM approach to neuro-developmental and psychiatric disorders is developed--- that should help.

Also, if patients are getting more effective and comprehensive treatments --- they may be a lot easier to deal with.]

RCCX Theory and Giftedness: A Promising New Line of Research (2019)

"Because it appears that mast cell activation problems exist in the gifted population in greater frequency than in the general population, we urge those in the gifted populations with health issues not solved by drugs in those categories to discuss the possibility of mast cell activation problems with their doctors."

Dr. Anne Maitland -- Mount Sinai
Neuropsychiatric Manifestations of Mast Cell Activation Disease (MCAS)

Neuropsychiatric Manifestations of Mast Cell Activation Syndrome and Response to Mast-Cell-Directed Treatment: A Case Series (2023)

Abstract

Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence of 17%.

Mast cell chemical mediators lead to heterogeneous multisystemic inflammatory and allergic manifestations.

This syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others.

Although MCAS is common, it is rarely recognized, and thus, patients can suffer for decades.

The syndrome is caused by aberrant mast cell reactivity due to the mutation of the controller gene.

A case series is presented herein including eight patients with significant neuropsychiatric disorders that were often refractory to standard medical therapeutics. Five patients had depression, five had generalized anxiety disorder, and four had panic disorder.

Other psychiatric disorders included attention-deficit hyperactivity disorder, obsessive compulsive disorder, phobias, and bipolar disorder.

All eight patients were subsequently diagnosed with mast cell activation syndrome; six had comorbid autonomic disorders, the most common being postural orthostatic tachycardia syndrome; and four had hypermobile Ehlers-Danlos syndrome.

All patients experienced significant improvements regarding neuropsychiatric and multisystemic symptoms after mast-cell-directed therapy.

In neuropsychiatric patients who have systemic symptoms and syndromes, it is important to consider the presence of an underlying or comorbid MCAS [Mast Cell Activation Syndrome].

Atypical response to the common Epstein-barr Virus --- Auto-immune Disease, Cancer & Major Mental Illness

4/18/2025

Val's Take/Conjecture

It's estimated that 90 to 95% of the population have the Epstein-Barr Virus.
So the virus itself is far from rare --- what's rare in various diseases and disorders is an ATYPICAL RESPONSE to the Epstein-Barr Virus.

Further, Epstein-Barr often becomes a problem for people but often in the context of "Aging."
For younger people and re-activated Epstein Barr Virus as well as re-activated Microglia -- this may be a form of premature aging.

For people with Neuro-Developmental and Psychiatric Disorders, their Microglia may have been dysregulated IN UTERO and easily re-activated.

AUTO-IMMUNE DISEASE

Multiple Sclerosis (MS) is now greatly associated with the Epstein-Barr Virus.
Further, there is some overlap between MS and Bipolar Disorder.

Autoimmune responses to myelin-associated proteins as diagnostic and prognostic biomarkers of relapsing-remitting multiple sclerosis: Associations with human herpesvirus-6 and Epstein-Barr virus reactivation (2025)

Multiple sclerosis and bipolar disorder: an overlap between soma and psyche (2024)

"This clinical vignette with literature review is an illustration of the interesting, yet still unknown relationship between MS and affective disorders, where one might be influenced by the other but also have a common pathophysiology.

"This highlights that the dividing line between neurology and psychiatry, whose pathophysiology often takes place in the same organ, is often arbitrary."

Does Epstein-Barr virus and intracellular Toll-like receptors affect the course of Hashimoto [Thyroiditis] disease? Findings from studies on newly-diagnosed patients (2024)

Microglia as potential key regulators in viral-induced neuroinflammation (2024)

Awakening the sleeping giant: Epstein–Barr virus reactivation by biological agents (2024)

PSYCHIATRIC DISORDERS

Hypothesis: bipolar disorder is an Epstein-Barr virus-driven chronic autoimmune disease - implications for immunotherapy (2020)

Microbes and Mental Illness: Past, Present, and Future (2023)

"Perspectives on the etiology of mental illness have evolved from demonic possession toward multisystem biologically based models that include gene expression, environmental triggers, immune mediators, and infectious diseases.

"Microbes are associated with a number of mental disorders, including autism, schizophrenia, bipolar disorder, depressive disorders, and anxiety disorders, as well as suicidality and aggressive or violent behaviors. "

Atypical immune response to Epstein-Barr virus in major depressive disorder (2020)

CANCER

Epstein-Barr virus lytic replication and cancer (2025)

"Epidemiological studies have provided strong evidence that Epstein-Barr virus (EBV) lytic replication is linked to cancer development."

Thyroid Issues In Mental Health

4/17/2025

Val's Take/Conjecture:

These "Thyroid" issues in Mental Health are critical.

In the Denver metro, there are some doctors who have made careers out of treating complicated thyroid issues.

When we talk about ADHD, Autism, Bipolar Disorder, Depression and Schizophrenia being Developmental, Multi-System Neuro-Immune Disorders --- one of those other systems is the Endocrine System.

Endocrine System

Shrinks in Sneakers
(Dr. Garrett Rossi)
Thyroid Hormone in Major Depression and Bipolar Depression

microplastics, Microglial activation and Environmental toxins --- bigger issueS than we normally think

4/11/2025

Val's Take/Conjecture

When we think about Neuro-Developmental and Psychiatric Disorders --- there is not 1 gene or 1 environmental factor or epigenetic factor that accounts for everything.
- This very much sounds like Stanford Biology and Neurology Professor Robert Sapolsky --- "It doesn't work that way."

Many Neuro-Developmental and Psychiatric Disorders are being conceptualized as beginning IN UTERO and then having "a life of their own."

Environmental Toxins

9 News (Feb. 2025)
New study of human brains shows there are enough microplastics to make a spoon

["Life style choices" are important -- BUT if we don't understand how dysregulations IN UTERO affect lifestyle choices across the lifespan and make people more vulnerable to various disorders and diseases as a result of these prenatal dysregulations ----- there is a high likelihood we're going to get a partial, misleading answer.]

NLRP3 inflammasome as a sensor of micro- and nanoplastics immunotoxicity
(2023)

Polystyrene nanoplastics penetrate across the blood-brain barrier and induce activation of microglia in the brain of mice (2022)

[Are microplastics inducing perpetual activation of microglia in the brain?]

The Graduate (1967)
One word -- Plastics

Tomorrow’s Cure: How a lifetime of exposures impact health – exposome explained (2024)

Fitzgerald Lab
Division of Innate Immunity

Biology and Function of Inflammasomes

Polystyrene microplastics induce anxiety via HRAS derived PERK-NF-κB pathway (2024)

Microplastics in the Air May Be Leading to Lung and Colon Cancers

A review of 3,000 studies also suggests these minute plastic air particles may be causing male and female infertility.

Exposure to nano-polystyrene during pregnancy leads to Alzheimer's disease-related pathological changes in adult offspring (2025)

lactoferrin ---Selected recent research

4/11/2025

Val's Take/Conjecture

NOTE: I am NOT a doctor --- I'm not recommending any treatments.
On the other hand, I am recommending we investigate Lactoferrin further.

This is complicated, of course.

There is a study from 1982 showing that people with schizophrenia have MORE LACTOFERRIN.

At the time, this was thought to reflect an abnormal inflammatory response in people with schizophrenia.

Elevated serum levels of lactoferrin and eosinophil cationic protein in schizophrenic patients (1982)

See also:

Global Bibliometric and Visualized Analysis of Research on Lactoferrin from 1978 to 2024 (2024)

Lactoferrin deficiency during lactation increases the risk of depressive-like behavior in adult mice (2023)

Lactoferrin alleviates Western diet-induced cognitive impairment through the microbiome-gut-brain axis (2023)

"Thus, Lf [Lactoferrin] intervention alleviated cognitive impairment by inhibiting microglial activation and neuroinflammation through the microbiome-gut-brain axis."

The Lactoferrin Phenomenon-A Miracle Molecule (2022)

Abstract

Numerous harmful factors that affect the human body from birth to old age cause many disturbances, e.g., in the structure of the genome, inducing cell apoptosis [programmed cell death] and their degeneration, which leads to the development of many diseases, including cancer.

Among the factors leading to pathological processes, microbes, viruses, gene dysregulation and immune system disorders have been described.

The function of a protective agent may be played by lactoferrin as a "miracle molecule", an endogenous protein with a number of favorable antimicrobial, antiviral, antioxidant, immunostimulatory and binding DNA properties.

The purpose of this article is to present the broad spectrum of properties and the role that lactoferrin plays in protecting human cells at all stages of life.

Unlocking the power of Lactoferrin: Exploring its role in early life and its preventive potential for adult chronic diseases (2024)

Abstract

Nutrition during the early postnatal period exerts a profound impact on both infant development and later-life health.

Breast milk, which contains lactoferrin, a dynamic protein, plays a crucial role in the growth of various biological systems and in preventing numerous chronic diseases.

Based on the relationship between early infant development and chronic diseases later in life, this paper presents a review of the effects of lactoferrin in early life on neonates intestinal tract, immune system, nervous system, adipocyte development, and early intestinal microflora establishment, as well as the preventive and potential mechanisms of early postnatal lactoferrin against adult allergy, inflammatory bowel disease, depression, cancer, and obesity.

Furthermore, we summarized the application status of lactoferrin in the early postnatal period and suggested directions for future research.

Lactoferrin alleviates the adverse effects of early-life inflammation on depression in adults by regulating the activation of microglia (2025)

"Our findings suggest that lactoferrin intake during lactation protects neurons by regulating microglial activation, thereby effectively reducing depressive symptoms in adults."

Lactoferrin Attenuates Pro-Inflammatory Response and Promotes the Conversion into Neuronal Lineages in the Astrocytes (2025)

Maternal Immune activation, Fetal Inflammatory REsponse syndrome

4/8/2025

and MULTI-SYSTEM Neuro-developmental & Psychiatric Neuro-immune developmental disorders

Exposure to Maternal Immune Activation Causes Congenital Unfolded Protein Response Defects and Increases the Susceptibility to Postnatal Inflammatory Stimulation in Offspring (2021)

Conclusion:

Overall, MIA exposure in utero caused failure in UPR [unfolded protein response] as well as immune overreaction to the second attack of inflammation in offspring.

Our results suggested that prenatal exposure to MIA might contribute to the congenital inflammatory constitution after birth.

The Unfolded Protein Response and Autophagy as Drug Targets in Neuropsychiatric Disorders (2020)

Targeting Cytokine-Mediated Inflammation in Brain Disorders: Developing New Treatment Strategies (2025)

"Cytokine-mediated inflammation is increasingly recognized for playing a vital role in the pathophysiology of a wide range of brain disorders, including neurodegenerative, psychiatric, and neurodevelopmental problems. . . .

"As research advances, the creation of personalized, cytokine-centered therapeutics has the potential to alter the therapy landscape for brain illnesses, giving patients hope for better results and a higher quality of life."

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders (2021)

Key points

Human studies are uncovering a role for maternal immune activation (MIA) in the pathogenesis of common neurodevelopmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome, in the offspring.

Prenatal, in utero and postnatal embedding of environmental factors in the epigenetic architecture of both the brain and the peripheral immune system can modulate individual susceptibility to neurodevelopmental disorders.

The effects of MIA, mediated by acute and chronic inflammation in pregnancy, are transduced to the fetus through inflammatory cell signalling pathways and epigenetic mechanisms.

Pathogen-associated molecular patterns, damage-associated molecular patterns and Toll-like receptors represent a convergent cellular pathway between heterogeneous environmental factors and innate immune activation.

In conjunction with individual genetic risk, sex-related factors and second ‘immune’ hits during life, MIA-induced aberrant immune programming results in a loss of immune homeostasis, which is associated with behavioural abnormalities in animal models.

Fetal inflammatory response and risk for psychiatric disorders (2023)

Children born to placentas meeting criteria for FIRS [Fetal Immune Response Syndrome] were more likely to be diagnosed with neuropsychiatric disorders.

Specifically, they were more likely to be diagnosed with

autism spectrum disorder,
conduct disorder,
adjusting for maternal history of
- psychiatric disorders,
- intra-partem substance use, and
- prescriptions of anti-inflammatory drugs.
Children born with placental inflammation are at an increased risk to develop neuropsychiatric disorders.
This has profound implications for future research, and early detection, monitoring, and treatment in these children.

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