Guardians of the Brain

Relevance to Multiple Sclerosis, Long Covid, Brain Tumors, and Neuro-inflammation

After many decades of misguided thinking that the brain was “immune-privileged", denoting its existence as a separate compartment from the body’s immune system, we are seeing a cluster of new discoveries that help explain the pathogenesis of diseases and offer new paths to treatment of various brain and central nervous system conditions. The brain-to-body immune system axis is progressively getting deconvoluted and it’s exciting to think what will ultimately come of it for preventing or treating diseases.

Please note that I’ll be hosting my first Ground Truths Live Chat this week Wednesday, December 11th at 12 N EST, 9 AM PST. Hope you can join me.

Background

There is an immune cell reservoir in the brain that is localized to to the skull bone marrow, the 3 meninges layers (pia, arachnoid and dura) that covers the brain, and the choroid plexus (Figure, left panel below). These immune cells are constantly patrolling the brain from its border.

Left panel from Li and Right panel from Rong et al

The immune cells travel through vascular channels, cerebrospinal fluid, and specialized lymphatics of the brain (known as glymphatic), which communicates with the rest of the body. Recently. Ali Erturk and colleagues published their findings of persistence of the SARS-CoV-2 spike protein in the skull bone marrow and meninges in individuals long after Covid, leading to brain injury and inflammation (right panel above), as also demonstrated in the mouse model. Here’s a video showing the presence of the spike protein in the human brain (in red) in the skull bone marrow long after a Covid illness.

I wrote about that seminal finding when the report was in the preprint stage here. The brain manifestations of Long Covid are extensive, well beyond brain fog and cognitive deficits, reviewed here, but we remain without a treatment. That’s why new insights about the immune system and the brain could play out to be important.

Brain Peptides that Protect Against Autoimmunity

A fascinating discovery by Kim et al, published in Nature, was the existence of myelin basic protein (MBP) derived peptide fragments that bind to the major histocompatibility complex (MHC Class 2) training T cells to protect against autoimmunity. In the mouse model of multiple sclerosis known as experimental autoimmune encephalomyelitis (EAE) boosting specific MBP peptide fragments (specifically MBP 160-175) blocked the autoimmune response induced by myelin oligodendrocotye glycoprotein (MOG). The work was conducted in a specific strain of mice and it does not have imminent clinical translation to a therapeutic, but it introduces a new concept for exploiting the brain’s capacity to silence an autoimmune response. It also reinforces the immune homunculus theory proposed by Cohen a decade ago, that the adaptive immune system regulates the response to self-antigens, differently between healthy individuals and those with autoimmune diseases.

Schematic of myelin derived peptides by Wekerle and Kawakami

Programmed T cells

In this week’s Science, a new path to blocking untoward brain inflammation or revving up the immune response to cancer was delineated by selectively programming T cells that sense brain antigens and deliver payloads. The first step for this platform was to identify the specific brain antigens (such as brevican, BCAN), and subsequently to demonstrate therapeutic payloads for mouse models of glioblastoma, metastatic breast cancer and EAE (model of multiple sclerosis). This involved customized synthetic gene circuits (SynNotch) to detect the antigens and there was an impressive impact in all 3 models (2 cancer, 1 autoimmune) clearing the brain tumors or suppressing inflammation via interleukin-10 secretion.

In a separate report by the same group, led by Wendell Lim, the local immune response was similarly targeted (bottom of right panel below) with synthetic suppressor T cells. Among other examples, the efficacy of such an approach was evident by the protection of beta cell transplants in the autoimmune diabetes model.

The potential for a specific route to the brain to deliver therapies that dial up or down the immune response is notable and conveyed by their summary graphic, even extending to neurodegenerative diseases.

The Body-Brain Axis for the Immune System

I reviewed this important topic recently but to save you having to link, I’ll repost the relevant section.

In a Nature paper, Columbia University researchers unraveled the circuit for how immune activation in the body activates the brain. By injecting bacteria compounds into the abdomen (intra-peritoneal, I.P.) of mice that elicited inflammation and an immune response, a region in the brainstem was switched on, as seen by imaging.

The circuit involved the vagus nerve to the caudate nucleus solitaris (cNST) in the brainstem. When the neurons were activated, inflammation was reduced (by ~70%). In contrast, when the neurons were silenced, the immune response was unleashed, and there was a 3 to 10-fold increase in mediators (interleukin-6, IL-1beta, IL-10) of inflammation. There was reciprocity in the circuits with surveillance by cNST/vagal of inflammation signals in the body. That’s akin to a rheostat, a master dial function of the immune system. It’s even more refined than that. By single-cell sequencing it was found there are 2 discrete circuits within the vagus nerve which are divided for response to pro-inflammatory and anti-inflammatory molecules. In the ulcerative colitis (an autoimmune condition) mouse model, the same manipulations of the circuit led to inducing dramatic colitis or protection from inflammation.

As the authors asserted, “Most unexpectedly, this body-brain circuit modulates not only pro-inflammatory but also the anti-inflammatory response.” Accordingly, It’s been called a “black swan event” since the biologic circuitry details were not anticipated. The implications for defining this neuro-immune axis for immune balance are potentially important for better approaches to autoimmune diseases, Long Covid, and dysregulated immune system conditions.

Calling Immune Cells to the Brain

A surprise finding (at least to me), also recently published in Nature, was that after a heart attack, monocyte immune cells are recruited to the brain (to the thalamic lateral posterior nucleus, LPN) to induce deep sleep, which suppresses sympathetic nervous system outflow to the heart, and reduces heart inflammation. The monocytes secrete tumor necrosis factor which works on sleep-regulating neurons in the brain to amp up slow-wave, restorative, deep sleep. When sleep was disrupted in the mouse model there was reduction of heart function, as was also seen when monocyte recruitment was blocked. In people with acute coronary syndromes, healthy sleep patterns were associated with better heart healing.

T cell Exhaustion in Myalgic Encephalomyelitis

In people with ME/CFS, an impressive single-cell multi-omics study of T cells demonstrated T cell exhaustion (particularly ATAC-seq, highlighting the epigenetic impact), reflecting chronic viral infection.

From the PNAS paper, CPET = cardiopulmonary exercise test

This work opens up new potential therapies such as immune checkpoint inhibitors or metabolic interventions to restore CD8+ T cell function.

Synthesis

These 6 recent publications are instructive for how the immune system of the brain and body interact, no less introducing new ways to intervene, such as programmed brain-targeted T cells. Brain cancer and unbridled neuro-inflammation, in such conditions as multiple sclerosis or Long Covid, have posed huge challenges to successful treatment. Better understanding of the newly identified brain-body rheostats—the exquisite capability to dial up or down the immune response—be it through neural circuits, programmed T cells, or the recently discovered endogenous peptides that keep autoimmunity at bay, collectively represent a major advance. I hope that this brief review gives you a sense of some compelling progress in how the two most complex systems in our body interact, in ways that a few months ago we had no idea!

*************************************************

Thank you for reading and subscribing to Ground Truths. As I’ve learned recently talking with subscribers, many people still don’t realize that it’s a hybrid of newsletter/analyses like this, and podcasts, roughly alternating between each format.

The Ground Truths newsletters and podcasts are all free, open-access, without ads.

Please share this post with your friends and network!

Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they have greatly help fund our summer internship and educational programs.