Our Brain—Immune Axis Gets A Jolt

Last year there was a major discovery of circuitry for how our immune system in the body activates the brain. In the past couple of weeks we’re seeing progress in understanding how the brain controls the immune system, including the clinical relevance, the first of its kind, a new FDA approval. In this issue of Ground Truths I’ll review the recent reports that spotlight the pivotal role of reciprocal interactions between our brain and immune system.

I’ve recently written about the gut-brain axis and how the gut talks to the brain and the immune system. There’s a common thread, the vagus nerve, which as shown in yellow in the map below, connects the brain with various organs throughout the body, including rich innervation of the gut lining. Beyond the vagal circuitry, other neural connections connect the spleen, gut, liver, bone marrow and lymph nodes (←new review in Nature Reviews Immunology) can activate the immune system’s T and B cells, macrophages, dendritic cells, plasma cells, production of antibodies, and release of pro-inflammatory cytokines.

Below is an example of how the brain connects through the splenic nerve can rev up the immune system (PVN-paraventricular nucleus, AChR-acetycholine receptor, RAMP-receptor activity-modifying protein, TIMP-tissue inhibitor of metalloproteinase). The connections between the brain and immune system are not just neural mediated, but also occur via hormones and chemical signals, especially mediated via the brain’s hypothalamus-pituitary axis.

With that anatomic basis, let’s get into the new reports and advances.

1. Just seeing a person with signs of infection activates our immune response!

This week in Nature Neuroscience Andrea Serino and colleagues published the results of 248 healthy volunteers who underwent virtual reality to see human avatar faces categorizing persons with signs of infection (coughing, rashes), one of fear, and another of neutrality (“Neural anticipation of virtual infection triggers an immune response.”). The participants underwent functional MRI, EEG and immune system studies. The infectious avatars activated the hypothalamic-pituitary axis which led to immune activation, replicated by flu vaccine administration, as seen below by innate lymphoid cells (ILC) and verified by multiple markers of lymphocytes. That wasn’t evoked by the neutral or fearful avatars.

2. An implantable neuroimmune modulation device for autoimmune disease

Last year Peterson and colleagues published a randomized, double-blind, sham controlled trial of an implantable 1 inch device to stimulate the vagus nerve in 60 patients with rheumatoid arthritis to show feasability and safety. Using the same double-blind, sham design, a Phase 3 trial was undertaken enrolling 242 patients with moderate to severe rheumatoid arthritis who had failed at least one advanced drug therapy (biologic or synthetic disease modifying drug). The device delivers stimulation for 1 minute each day and is recharged during 10 minutes each week wirelessly via a necklace (schematic below).

At 12 weeks, 35% of patients receiving daily stimulation vs 24% of the sham device achieved improvement in the ACR20 endpoint (American College of Rheumatology 20% response criteria). For the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) endpoint, the treatment group had a 27% response vs 16% in the control group. By 1 year, with crossover all to the active device, over 60% of participants had relief of joint pain and swelling. The main adverse effect was hoarseness, which occurred in 2% of participants due to the device implant.

SetPoint Systems, the company that commercialized the device, received FDA approval this week and that was on the front page of the New York Times.

The company has also published efficacy results for the device in the experimental model of multiple sclerosis and have already initiated clinical trials for inflammatory bowel disease in children and lupus and plans to do clinical trials for multiple sclerosis and Crohn’s disease.

This is an outgrowth of the pioneering work of Prof Kevin Tracey who has been the main force over 2 decades to push the field forward. His classic paper in Nature in 2002 entitled “The Inflammatory Reflex” advanced the concept that vagal nerve stimulation could suppress inflammation.

3. The Alzheimer’s Disease Risk of APOE4 Carriers is Mediated via the Immune System

One copy of the APOE ε4 allele is present in about 20% of people and is the strongest genetic risk factor of late-onset Alzheimer’s disease. That discovery was made in 1993 but the mechanism for how the ε4 allele induces the risk has not been clear in the three subsequent decades. In Nature Medicine, Shvetcov and colleagues demonstrated that carriers of the ε4 allele have a proteomic signature denoting immune dysregulation. From machine learning of nearly 10,000 plasma samples and >1,300 cerebrospinal fluid (CSF) samples, there was convergence of many findings between plasma (shown below) and CSF, and a pro-inflammatory signature was seen. There was marked immune cell enrichment, predominately T cells, monocytes, and natural killer cells. This finding reshapes our understanding for how the APOE ε4 allele increases the risk of neurodegenerative disease.

Parenthetically, another clarification for an elusive mechanism of action (MoA), there was a reset for how metformin works. As the first line drug for Type 2 diabetes used for 60 years, there were many ideas for its MoA such as reducing glucose output from the liver. We just learned metformin relies on a pathway in the brain to exert its effect.

4. A Multiomics Study for Alzheimer's and Cerebrovascular Diseases

A new paper in Neuron examined RNA and epigenetic variants for Alzheimer’s (AD) and stroke (study schematic below) and found that the former was linked to dysregulated immune system omics, with a lead variant that enhanced expression of PTK2B in brain T cells. The evidence for altered adaptive immunity for AD was in marked contrast to the findings for omics related to cerebrovascular diseases, and provides yet another study highlighting the immune system’s status as off the track for AD.

Other Related Reports

A randomized trial of structured lifestyle improvement with coaching for an anti-inflammatory diet, exercise, as compared with controls who were self-guided, showed significant improvement in global cognition.

A study of ME/CFS by Akiko Iwasaki and colleagues, using plasma and CSF samples of affected individuals and matched controls, demonstrated 2 distinct immunotypes for this condition, which is characterized by many symptoms that are referable to the central nervous system.

A randomized trial of semaglutide (Ozempic) vs placebo in participants with HIV-associated lipohypertrophy, a pro-inflammatory condition (mean BMI of participants =33 ) was preprint published. The GLP-1 drug slowed epigenetic aging and the pace of aging across 11 organ and system clocks. This likely reflects the potent anti-inflammatory effects of these drugs, both systemically and in the brain. The significant slowing of the pace of brain aging (nearly 5 years) is shown below at right. As far as I know, this is the first drug in a randomized, placebo-controlled trial to demonstrate such epigenetic and organ clock findings. Clearly, we’ll need to see independent replication in healthy individuals who are not overweight or obese, but these results are nonetheless encouraging.

Concluding Remarks

In my book Super Agers, I have a chapter on “Controlling Our Immune System” which goes through the ways we are taking control of our immune system like a rheostat. Dialing it down to achieve tolerance in autoimmune diseases, such as engineered T cells that bind to a protein on the surface of all B cells (CD-19). That has achieved remarkable success in a small number of individuals with several autoimmune diseases (lupus, multiple sclerosis, polymyositis, and others). In prior Ground Truths posts, I’ve reviewed other ways we can dial down the immune response, such as through the liver (!) or tolerogenic vaccines. Here, the studies on vagal stimulation have now validated yet another approach that we can suppress the immune system and inflammation and the indication for rheumatoid arthritis is likely just the beginning. Perhaps there will be simpler, inexpensive, non-implantable devices to achieve vagal nerve stimulation such as was anecdotally reported for Long Covid. We’re also learning about how the GLP-1 drugs can be used to block inflammation, awaiting the results of the EVOKE Alzheimer’s randomized trials next month.

Just as our armamentarium is expanding for suppressing the immune system, we’re seeing how it can be dialed up too. For example, the results of the 3 natural experiments of Shingles vaccines that consistently lowered the rate of dementia and Alzheimer’s disease, reviewed here, or how more aggressive ways to rev up the immune system are leading to heightened treatment success for refractory cancers. However, there’s a fine line for unleashing the immune system with the potential of promoting a self-directed or dysregulated state. Despite that critical concern, we’re making major strides in controlling our immune system.

Ironically, we still don’t have a way to measure it routinely, as I conveyed in Why We Need an Immunome. That remains a huge hole in the story for how we’re going to be able to promote healthy aging. Here, for example, I’m referring to the need to detect the degree of immunosenescence in older adults that poses a vulnerability for cancer and other age-related diseases. With all the new data pouring in for the primacy of the immune system, we need to accelerate ways to get a handle on a person’s immune system status.

That brings me to the recent organ clock paper on the plasma proteomics of healthspan and longevity. In 17-year follow-up of the ~45,000 UK Biobank participants, assessing 8 organs (including heart, kidney, artery, brain, liver, pancreas, lung and immune system). Slow aging of the brain or immune system was linked with the best survival (Figure) and there was also evidence that slow paced aging of both the brain and immune system provided additional benefit beyond each alone.

I hope I’ve convinced you that through a variety of different studies, the brain-immune axis has emerged as more important than previously acknowledged. That’s noteworthy as a root cause of neurodegenerative diseases and for coming up with improved treatments. It’s giving us a great foundation to build on to prevent these diseases in the future and promote healthy aging.

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Thanks to many of you Ground Truth subscribers who helped put SUPER AGERS on the NYT bestseller list for 4 weeks so far. Here’s a new segment I did on PBS about extending healthspan and the new Notebook LM A.I. generated video summary that integrates both the book and Ground Truths for the Secrets of Super Agers!

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