Immune Driven Psychopathology in Mice?

It all began way back in the 19th century. "Sickness Behavior" was observed in humans and farm animals. As that Wiki article goes on to explain, there are some interesting similarities between sickness behavior and depression. This has been an active area of research for many years now. One key article is this one from 2003. This strange and puzzling linkage between the nervous systems and immune systems has been evidenced by the following:

• Shizophrenia is associated with differing rates of cancer and autoimmune disease from others.
• Epileptics also have altered immunological responses, this possibly driven by hippocampal - fornix - PVN networks(guess).
• Traumatic brain injury can induce a variety of physiological changes, from altered melatonin production to variations in circadian cortisol secretion. 

This is going to be difficult ...


I haven't looked at neuroimmunology for sometime but this recent news release caught my interest because it highlights, apparently, a very direct linkage between immunological function and psychopathology; at least in a species of mice. This is the central claim:

Capecchi and colleagues showed that pathological grooming and hair-pulling in mice – a disorder similar to trichotillomania (trick-o-til-o-MAY-nee-ah) in humans – is caused by a mutant Hoxb8 gene that results in defective microglia, which are immune system cells that originate in bone marrow and migrate from blood to the brain. Microglia defend the brain and spinal cord, attacking and engulfing infectious agents.

This being proved by:

In the key experiment, geneticist Shau-Kwaun Chen, Capecchi and colleagues transplanted bone marrow from normal mice into 10 mice that had a mutant Hoxb8 gene and compulsively pulled out their own chest, stomach and side fur. As the transplant took hold during ensuing months, grooming behavior became normal, four mice recovered completely and the other six showed extensive hair growth and healing of wounds.

“A lot of people are going to find it amazing,” says Capecchi. “That’s the surprise: bone marrow can correct a behavioral defect.”

Some important points about microglia:

• 60% of all microglia arise from developmental processes in the CNS.
• The other 40%  migrate to the CNS at various stages of life.
• There is evidence to indicate that microglia can adopt a dendritic cell morphology, which has strong implications for sustaining an inflammatory response as dendritic cells release il-12, a cytokine can stimulate pro-inflammatory cytokine production. 
• Microglia outnumber neurons by 9 to 1. 
• It has long been known that microglia have indirect impacts on neural function, but of course what constitutes "indirect" here is very difficult to accurately determine! 

In the above study it was a specific change in the HOX8B gene that caused the excessive grooming, not unlike a human condition known as trichotillomania and is considered to be an obsessive compulsive disorder. This gene belongs to a class of genes known as homeobox genes, a class with regulates the expression of many other genes. Perhaps it was the developmental impact of this gene's absence that caused the behavior. For current purposes though we'll run with the appealing assumption.


This is where we run into grief:

In the new study, the Utah geneticists concluded that compulsive grooming and reduced sensitivity to pain were due to separate malfunctions of the Hoxb8 gene; the bone marrow transplants that cured hair-pulling did not restore the loss of pain sensitivity.

What do we have now? One behavior can be cured by bone marrow transplant which results in microglia with a functional HOXB8 gene migrating to the CNS and eventually correcting the behavior. This was not the case for sensitivity to pain, which arose from the spinal cord:

Mutating Hoxb8 in the spinal cord resulted in reduced sensitivity to pain, but not compulsive grooming.

Perhaps it is the case that the cells arising from the transplanted bone marrow just didn't reach the spinal cord tissue. Another possibility is that the spinal cord, particularly the dorsal root ganglion cells, appear rather susceptible to sustaining neuropathic pain and there is a lot of evidence to indicate that microglia plan a key role in mediating neuropathic pain. So once the inflammatory process has been initiated, even the presence of the non-mutant microglia may not be sufficient to prevent the increased sensitivity to pain. 


Whiplash injury is the most obvious example of this process, it can take years to unfold but eventually the patient reports with considerable pain yet there no discernable physical injury by various imaging modalities. It is as if a slow degenerative process has been set in train that eventually results in symptoms becoming apparent. With regard to the nervous system this long slow decline is the norm not the exception. It is evidence in a wide variety of neuropathologies including Multiple Sclerosis, Parkinson's Disease, Alzheimers, and even in major depression there can be very noticeable cerebral atrophy in the temporal lobes; specifically the hippocampus. 


Another issue here is whether or not these microglia are performing all the roles they are believed to perform. These are amazing cells, capable of supporting the most metabolically active cells for a lifetime whilst simultaneously acting as defenders of the realm and garbage collectors. While it is commonly accepted that immunological activation in the CNS is typically a bad thing there are now a number of studies suggesting that microglial activation plays a very important role in amyloid scavenging, amyloid being the suspected protein in Alzheimers(recent research is now pointing to a. oligomers as the real culprits). One recent study even found that "massive gliosis" induced amyloid scavenging yet such a state of microglial activation is typically regarded as a disaster for neighbouring neurons. It has long been accepted that inflammation is a precursor to dementia but there is evidence mounting that inflammatory processes are not only fundamental in pathogen defence but also in growth and repair processes. It is probably the case that inflammation can be both a cause and consequence of Alzheimers. That is the easy way out. 


Strictly speaking inflammation is a concept we should abandon because it bundles together physiological events that are better perceived in isolation. The sad truth is that using the word "inflammation" as a pointer to a physiological condition is another example of where words and their everyday meaning have little relation to a technical meaning but that doesn't stop the use of that word leading our thinking astray perhaps the Whorf Sapir Hypothesis was onto something after all dammit. 


Another function of microglia, one I still find hard to believe, is indicated in the below abstract. It means this: 


All cells create waste products that must be either degraded or removed. One key way this is achieved is through the lysosomal pathway. Lysosomes are internal regions of a cell that degrade various lipoproteins. This degradation process is metabolically very expensive and lysosomes do fail, leading to lysosomes becoming overloaded with waste products. This is potentially very dangerous because a lysosome can burst and released its highly acidic contents into the cell cytoplasm. This is so dangerous that lysosomes used to be known as "suicide vesicles" because upon bursting they could kill a cell. 


In the below article they argue that as the lysosomes in neurons become overloaded these lysosomes are moved to the cell wall where a waiting microglia absorbs the lysosome. The microglia will then migrate to a capillary and dump the lysosomal contents into the blood stream! Now that's dazzling stuff which is why I have difficulty accepting the claims of the below abstract.

Ann N Y Acad Sci. 2006 May;1067:383-7

    Processing, lysis, and elimination of brain lipopigments in rejuvenation therapies.

    Riga S, Riga D, Schneider F, Halalau F.

    Department of Stress Research & Prophylaxis, Al. Obregia Clinical Hospital of Psychiatry, Bucharest, Romania.

    Cerebral lipopigments (LPs)--lipofuscin and ceroid--represent a significant marker in postmitotic normal and pathologic aging, connected with causal and associated neuropathologic damage. Therefore, LP processing, lysis, and elimination may be the main targets in anti-aging and rejuvenation therapies. The regenerative neuroactive factors improve neuron supply with specific nutrients from plasma. They enhance the antioxidative defense, have anti-LP-poietic actions, stimulate brain anabolism, support energetic metabolism, and elevate the reduced lysosomal enzymes. In the second stage, by cytoplasm rehydration, they initiate the breaking up of the neuronal aggregated LP conglomerates, by consecutive disintegration. Then, possibly by the localized exo-endocytosis process between neurons and adjacent glia (especially microglia), intercellular LP transfer can be realized. So, therapeutically activated glia turn into brain garbage collectors and transporters. Therapeutic processing of glial LPs increases in the capillary neighborhood. Highly processed LPs, by glio-endothelial transfer, reach capillary walls before being eliminated. Consequently, neuroactive therapies having these synergistic rejuvenative actions represent new prospects in deceleration of normal and pathological cerebral aging.    PMID: 16804015 [PubMed - indexed for MEDLINE

Now if the above paper had been published in "Medical Hypotheses" I might have been more inclined to dismiss it, but given recent findings that lipofuscin and drusen("drusen" is a compound often visible in aging eyes and if too extensive can suggest AMD is emerging) can be reduced by various strategies it is plausible that there have evolved processes that allow a complex elimination process of lipofuscin; especially as lipofuscin is the cardinal marker of cell aging. Don't worry about the DNA, if a cell is loaded with lipofuscin no amount of healthy DNA will save it. 


So what of the HOX8B experiment? Great stuff, informative and interesting, but ultimately we are a very long way from understanding the relevant causal factors giving rise to the results. What is clear is that we can no longer perceive our behavior as simply a product of our brains, it is the product of our whole physiology acting in concert with the environment. We will need to abandon concepts like "inflammation" and we will need to completely re-evaluate what we mean by the "immune system".