Brain Drain

The brain contains lymphatic vessels similar to those found elsewhere in the body, a mouse study shows.

By | June 1, 2015

Mouse brain top viewWIKIMEDIA, DATABASE CENTER FOR LIFE SCIENCEThe mammalian brain, long thought to lack a lymphatic system, contains canonical lymphatic vessels that bear the molecular markers of the structures that carry fluid and immune cells from the tissues to the lymph nodes elsewhere in the body, according to a mouse study published today (June 1) in Nature.

“For many years, we said ‘There’s no lymphatic drainage from the brain,’” said Jon Laman, an immunologist at Erasmus University Medical Center in Rotterdam, the Netherlands, who was not involved in the work, “but this, in a way, is a breakthrough study because it shows the presence and functionality of a lymphatic vessel in the dura mater.” Of the meninges, the three membranes surrounding the brain, the dura mater is the one closest to the skull.

“These structures are bona fide vessels—they express all the same markers as lymphatic vessels in every other tissue, and they drain the CSF, the cerebrospinal fluid, from the brain and the spinal cord into the deep cervical lymph nodes,” said Jonathan Kipnis of the University of Virginia School of Medicine, who led the work. “So there’s a direct connection between the CSF and the draining lymph nodes.”

The relationship between the brain and the immune system has long puzzled researchers. For some time, scientists thought that immune cells only showed up in the brain during an infection. The brain is considered “immune privileged,” such that when exposed to foreign material, it takes longer to mount an immune response than does the rest of the body. Furthermore, to date, traditional lymphatic vessels had not been found there.

Several nontraditional routes of fluid circulation in the brain have been described, however. In recent years, neuropathologists Roxana Carare and Roy Weller of the University of Southampton, U.K., reported a system by which CSF—produced in the ventricles—exits the brain via the mucous membranes of the nose and by which interstitial fluid (ISF)—solute-bearing liquid filtered from the blood—leaves by traveling along the basement membranes of capillaries and cerebral arteries. In 2012, Maiken Nedergaard of the University of Rochester Medical Center in New York and her colleagues reported that the circulation of CSF and ISF in the brain was facilitated by water channels in the glial cells that abut the brain vasculature, and coined the term “glymphatic system.”

The Kipnis team’s latest finding represents an additional lymphatic pathway for the brain. Working in mice, Kipnis and his colleagues found that vessels expressing markers of lymphatic vessels elsewhere in the body ran along the dural sinuses, drainage lines in the brain that collect outgoing blood and CSF, emptying these fluids into the jugular vein. They also found that the vessels contained immune cells.

The researchers also probed the circulatory pathways of these vessels by injecting mice with two different tracers—one intravenously, to the circulatory system, and one into the subarachnoid space, a fluid-filled space between the inner two meninges. The tracer injected into the brain stained the newly discovered lymphatic vessels, indicating that CSF passes through them, while the intravenous dye stained separate blood vessels.

Further, the researchers injected Evans blue dye into the subarachnoid space and found that it stained the deep, though not the superficial, cervical lymph nodes. Investigating this pathway from the other direction, they sewed together channels of the cervical lymph nodes and found that fluid backed up in the new lymphatic vessels.

Carare, who was not involved in the study, noted that in a previous study led by Weller, tracer injected into the subarachnoid space traveled to the cervical lymph nodes through the nasal route. “The presence of Evans blue in the present study may be a result of a combination of drainage mechanisms and pathways,” she wrote in an e-mail to The Scientist.

CSF drainage through the nasal pathway “may represent a highly specialized system of the dural lymphatics described in this paper,” Carare added.

While much remains to be worked out, Kipnis noted that, at the very least, these latest results add to mounting evidence of immune activity in the healthy brain. “If you go into the literature, 20 years ago, the idea was that if you see immune cells in the brain, something must be going wrong,” he said. “Now we know that we see immune cells in healthy brains. . . . It’s part of normal physiology; it should be there. Immune activity in the brain is not always pathological.”

A. Louveau et al., “Structural and functional features of central nervous system lymphatic vessels,” Nature, doi:10.1038/nature14432, 2015.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 350

June 2, 2015

Re:

“If you go into the literature, 20 years ago, the idea was that if you see immune cells in the brain, something must be going wrong...”

In our 1996 Hormones and Behavior review article, we wrote:

Immunological Factors

The immune system has long been known to perceive certain sexual differences, e.g., the presence or absence of H-Y antigen (Simpson, 1991). Mice have been shown to enact kin selection on the basis of major histocompatibility complex characteristics within the perceiving mice and from other mice as chemosensitive identified. Humans have been shown to possess similar immune- related chemosensitive skills (Gilbert, Yamazaki, Beauchamp, and Thomas, 1996; Wedekind, Seebeck, Bettens, and Paepke, 1995).

Gilbert’s group found that humans could detect differences in individual chromosomes from otherwise syngeneic mice, including on the basis (i) of differing X or Y chromosomes or (ii) of differences introduced as nonidentical MHC haplotype (Gilbert et al., 1996). Wedekind et al. (1985) found that human females who were not taking oral contraceptives would select male-scented T-shirts in direct relationship to the males’ MHC-haplotypic difference from each perceiving female’s own MHC-haplotype. This indicates a dual awareness by the perceiver, i.e., of her own haplotype and of haplotypes sensed as different from her own. These findings establish that immunological components have the capacity, at a subconscious level, to contribute to adult human sexual interactions.

In 1985, science fiction author, Greg Bear began to link these RNA-mediated events to virus-driven cell type differentiation and continued to do so in three novels.

1) Blood Music

2) Darwin's Radio

3) Darwin's Children

Everything currently known about physics, chemistry, and the conserved molecular mechanisms of RNA-mediated cell type differentiation in all genera links viral microRNAs to entropic elasticity and the anti-entropic epigenetic effects of nutrient-dependent microRNAs to cell type differentiation in all cells of all individuals -- including cell type differentiation in brain cells via links between the immune system and the RNA-mediated biophysically constrained chemistry of nutrient-dependent protein folding.

Avatar of: N K Mishra

N K Mishra

Posts: 57

June 3, 2015

Cerbrospinal fluid is in dyamic circulatation in and around the brain to perfuse and  exert right intracranial pressure. This fluid is akin to lymph.No wonder the layers that surround the brain(dura mater, arachnoid membrane and pia mater) are permeated through extremely fine channels.

Avatar of: James V. Kohl

James V. Kohl

Posts: 350

July 13, 2016

Shocking new role found for the immune system: Controlling social interaction

Excerpt: "The brain and the adaptive immune system were thought to be isolated from each other... And now, not only are we showing that they are closely interacting, but some of our behavior traits might have evolved because of our to pathogens... "It's crazy, but maybe we are just multicellular battlefields for two ancient forces: pathogens and the immune system. Part of our personality may actually be dictated by the immune system."

No one who read our 1996 Hormones and Behavior review is likely to have continued to think that the brain and the innate immune system were isolated from each other.  Our section on molecular epigenetics set the stage for others to claim Feedback loops link odor and pheromone signaling with reproduction.

Placing claims like that back into the context of neo-Darwinian theories is even more innappropriate this year. You can't get to the feedback loops via mutations and natural selection. So, how could evolution establish them?

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