More than two million Americans are currently diagnosed with schizophrenia, a serious mental illness that interferes with a person’s ability to think clearly, manage emotions, make decisions, and relate to others.
Mike Hedric, author of the book Connections (The Journey of a Schizophrenic), poignantly describes in the New York Times his own experience with a mental illness that does not allow to distinguish what is real from what is imagined: “Schizophrenia is the devil on your shoulder that keeps whispering in your ear and, no matter what you try, the little demon won’t stop. He hasn’t stopped in the almost nine years I’ve lived with the illness, and he’s not about to stop now. He’s just quieted down a bit. I’d call him my companion but that would imply a degree of friendship, and there’s no way in hell I’m the little devil’s friend.”
Image credit: CHRISTIAAN TONNIS, CC BY-SA 2.0
Schizophrenia is a chronic brain disorder that affects about one percent of the population. Most commonly, schizophrenia occurs in late adolescence and early adulthood. When schizophrenia is active, symptoms can include delusional thinking, hallucinations, trouble with thinking and concentration, and lack of motivation. Hearing voices (“the devil on your shoulder that keeps whispering in your ear“), or auditory hallucinations as psychiatrists call them, is a common experience for people living with schizophrenia. In fact, it is so common that it is considered to be one of the principal indicators when considering a diagnosis.
When symptoms are treated, most people with schizophrenia greatly improve over time. However, the currently available drugs only control some of its symptoms—they do not act on the underlying causes of the disorder. But what causes schizophrenia? While the causes are unknown, it is known that there is no single cause. Rather, a combination of brain chemistry and genetic and environmental factors are likely to be responsible for the development of this mental illness. Results from a recent study pinpoint some of these possible factors. One of these studies, published in the journal Nature a little more than a month ago, has been touted as a significant advance in understanding the cause of schizophrenia. indeed, the study (Schizophrenia risk from complex variation of complement component 4) provides considerable insight into biological factors related to the immune system that could be involved in the development of psychiatric disorders. Specifically, the study results indicate that the development of schizophrenia is linked to excessive activity of the complement system.
The complement system plays a major role in immunity, leading to killing of infectious microbes and to regulation of inflammation. Thus, it participates in the development of integrated and effective immune responses. The complement system is made up of different proteins, and the scientists found that the gene that codes for one of these proteins, C4, is linked to schizophrenia. This gene, which is composed of two components, C4A and C4B, was considered a prime suspect in the search for causes of psychiatric disorders because it is present in distinct variants within the human population. Therefore, different individuals may have not only variable numbers of copies of the gene, but also unique DNA sequences, causing the gene to work differently.
According to the study results, people with schizophrenia have a C4A gene variant that facilitates synaptic pruning. This is a process in which the brain eliminates weak or redundant connections between neurons as it develops to full maturity in late adolescence and early adulthood. Noticeably, as previously mentioned, the onsets of schizophrenia symptoms occurs in late adolescence and early adulthood. In addition, individuals with schizophrenia have a reduced numbers of synapses in their brain. Thus, the findings related to C4A provide a plausible biological explanation for the onset of schizophrenia.
Bruce Cuthbert, acting director of the National Institute of Mental Health, said in a press release: “This study marks a crucial turning point in the fight against mental illness. It changes the game. Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments and even prevention.”
Schizophrenia is often diagnosed in early adulthood and causes a deception in reality where people often suffer from hallucinations and dysfunctional thinking. I often see patients in the emergency department who are suffering from schizophrenia and hear voices telling them to do things that a logically thinking person would not normally do. There have been many suggestions of causes including genetic and environmental factors. The complement system as a possible factor is a remarkable field of study for this mental illness. The complement system has three different pathways with each pathway playing a different role in inflammation, opsonization, and lysis of foreign cells. The original study states that there is excessive activity of the complement system in those suffering from schizophrenia particularly there is variability in the C4A gene coding for the complement protein C4. The C4A gene is responsible for reducing synaptic connections during early adulthood. In another study, it also shows how there could be a correlation between increased complement system activation and schizophrenia. It looks at hyperactivation of the alternative pathway and the activity level of C3 in those suffering from schizophrenia. It was found that there were increased levels of activation of both the alternative pathway and in C3 present in the blood of those with schizophrenia. Both studies propose that the complement system plays a role in this mental illness, so possibly they could be used as evidence for future studies focusing on controlling the complement system as treatment for schizophrenia.
http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml
http://eds.a.ebscohost.com/eds/pdfviewer/pdfviewer?vid=5&sid=31c23da5-35ca-4da8-a03c-1544e8ac7b31%40sessionmgr4002&hid=4102
It seems almost counter-intuitive to think that a psychiatric disorder such as schizophrenia would have any connection with the immune system. The fact that there is a connection shows how much there still is to discover about the relationships between the different body systems and exactly how much influence one has one the other. This study has suspected the C4 protein of the complement system as a possible source of schizophrenia onset due to the protein’s genetic variability. With that in mind, it should be clear that the study observed synapse degradation due to overactive C4 in mice only and suspected a parallel function in humans due to the presence of the human C4 protein in several parts of the neuron.
The claim that genetic variation in the C4 protein that is supposedly linked to the onset of schizophrenia raises some questions. One question involves the several possible consequences of such a variation. If it is possible for a variant C4 sequence to change the function of the protein so that the protein damages synaptic connections, then what other functions are possible for this protein. It could be that with the many variations in the C4 sequence, the protein is able to perform other functions, be they detrimental or beneficial.
It’s interesting that the C4A component of the C4 protein has become the primary target in regards to schizophrenia because this protein has also been associated with the autoimmune disorder, systemic lupus erythematosus. In this case however, the disease is brought upon by a deficiency in C4A as opposed to a genetic variation, as in the case with schizophrenia. Nevertheless, it seems that the participation of the C4 protein in some diseases begs the question of what other diseases is this protein involved in and what other proteins produce similar effects?
Though the article C4 component of the complement system has become a target for the study of the cause of schizophrenia, other studies have looked at the microglia due to its association with gray matter loss of the cortex. Along with synaptic pruning, as is described to be caused by the C4 proteins, microglia have been cited as a source of neuron engulfment, and insufficient release of nervous tissue growth factors. These characteristics are also indicative of schizophrenia. It’s not to say one is more right than the other, but fact that there is evidence of immune system components playing a part in schizophrenia proliferation underscores the importance of these studies. Further, it would be beneficial to broaden the scientific horizon in terms of discovering the involvement of certain body systems with other body systems to learn more about diseases.
The Search for Lupus Biomarkers
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727983/
Cortical gray matter loss in schizophrenia: Could microglia be the culprit?
http://www.ncbi.nlm.nih.gov/pubmed/26880628
I was also surprised there was a connection between the immune system and mental illness i.e. the brain. The skeptical part of me wonders if it’s just a correlation or an actual causation, the whole “correlation does not equal causation” saying but the research does seem highly credible. Your comment on how it would be beneficial to broaden the horizon had me thinking of all the possibilities this research could lead to. This research could be the start of the cure of schizophrenia, it could lead to the reestablishment of those lost synaptic connections not only that, it isn’t too far-fetched to think it could lead to the creation of artificial synaptic connections. Using this research could give more light on the total mechanisms of synapses and the artificial synapses could be used in prosthesis or maybe even artificial intelligence. Conversely, the synaptic connections could be manipulated in a way to improve the effect of the immune system. All due to bridging immunology and neurology!
Mental illness affects a large number of people in the world, however, the mechanism of action and cells involved are vastly unknown. Schizophrenia and mental illness in general is understudied and far less understood than most other physical diseases and illnesses. This makes sense since many aspects of the brain are still trying to be discovered. There is an overwhelming amount of information that is missing from our knowledge of the mechanism of action regarding many mental illnesses, but this new research providing evidence of complement protein interactions with neuronal connections is a large step in the right direction!
The research into the link between schizophrenia and a malfunction of the immune system seems far fetched at first. Since there seems to be a miscommunication between the complement proteins and neurons, schizophrenia may be considered an autoimmune disorder in that the host’s immune cells are destroying the host’s neuronal cells. The C4 protein over prunes the neuronal connections leading the alterations in the structure of the patient’s brain and lack of neuronal connections proves to lead to debilitating symptoms. Interestingly enough, while lupus and multiple sclerosis (MS) can be positively correlated with schizophrenia, indicating an issue with the innate immune response, rheumatoid arthritis and schizophrenia are not thought to be correlated based on the research conducted by James Paul Pandarakalam (in the article “The Autoimmune and Infectious Etiological Factors of a Subset of Schizophrenia”). Both disorders have correlations with MHC expressing genes. While most mental disorders involve many different aspects of immunity, gene mutation/variation and environmental factors, focusing in on one particular cause such as the complement system may establish new treatment techniques for patients. Perhaps including an anti-inflammatory or immune suppressing drug may help minimize some of the symptoms and damage in patients who begin experiencing symptoms of schizophrenia.
The Autoimmune and Infectious Etiological Factors of a Subset of Schizophrenia
http://ezproxy.gsu.edu/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=a9h&AN=113415074&site=eds-live
Your proposal of using an anti-inflammatory or immunosuppressing treatment for schizophrenia intrigued me to do further research. Upon researching, I found a study in which they are in the beginning stages of studying just that. In the study, they are assessing the possibility of using psychedelics as an anti-inflammatory therapeutic treatment for autoimmune and chronic inflammatory disorders including schizophrenia. Psychedelics are a drug family known as hallucinogens and include drugs such as LSD and ecstasy. The article shows that psychedelics are strong anti-inflammatory agents through their agnostic activity at 5-HT1, 5-HT2, and sigmar-1 receptors. These receptors are serotonin receptors which signal proinflammatory cytokines. It shows that these drugs could have the ability to diminish uncontrolled inflammation and upon further investigation and future studies then possibly the drugs could be used in treating these disorders.
http://eds.a.ebscohost.com.ezproxy.gsu.edu/eds/pdfviewer/pdfviewer?vid=2&sid=e9af10fc-f6e6-49e5-a485-69ccb8c3f45c@sessionmgr4001&hid=4113
As someone who has seen the damaging effects of schizophrenia through a family member, I find what the research, “Schizophrenia risk from complex variation of complement component 4” has proposed very interesting. The immune system is such a major component in individual health, but mental health was not something I had thought of. Upon further research, I found that mutations and variations of the C4 protein can be tied to other disease. Research from Breukink et.al 2015 showed that having no copies of the C4B gene increases the risk of chronic central serous chorioretinopathy (cCSC), an eye disease in which there is fluid accumulation under the neuroretina, which contains neuronal cells of the retina. The fluid accumulation causes the neuroretina to become detached. What I find revealing about this disease in which C4 gene variation is also at play is that it can also affect neuronal cells, but in a different part of the body. Breukink et.al 2015 also mentions that C4 gene variation is associated with other eye diseases and autoimmune disorders, like lupus as another poster mentioned.
I think it would have made an even more revealing and engaging article if the author’s had mentioned the associations of the C4B protein with schizophrenia, but they mostly focused on the C4a. One source published in 2008 revealed that C4B serum protein level is deceased in schizophrenic patients than compared to healthy patients. Exploring more molecular factors contributing to the pathogenicity of schizophrenia is a great route to go with this mental illness, and I think those with schizophrenia and their families want to know exactly what is causing this disease instead of the general factors of stress, genetic, and environment.
References:
Breukink, M. B., et al. (2015). “Genomic Copy Number Variations of the Complement Component C4B Gene Are Associated With Chronic Central Serous Chorioretinopathy.” Invest Ophthalmol Vis Sci 56(9): 5608-5613.
Mayilyan, K. R., et al. (2008). “Complement C4B protein in schizophrenia.” World J Biol Psychiatry 9(3): 225-230.
I like the fact that you mentioned that everyone seemed to have forgotten about the C4B complement’s association with schizophrenia. There has been research on C4b levels in schizophrenics showing lower C4b levels but in some other studies, there was no deficiency. The study with no deficiency involved both the schizophrenics and their mothers testing whether there’s a genetic component to the disease involving their maternal line.
What I found really interesting was a study on the correlation between higher levels of the C4b gene and the steroid cortisol. Patients with a particular C4b gene had higher levels of cortisol compared to the controls. Cortisol is a steroidal hormone typically released during stress. In another study it was also discovered that schizophrenics have higher levels of cortisol compared to non-schizophrenics thus hinting that cortisol metabolism plays a role. It is also known that schizophrenia has many causative factors including stress. This theory factors in stress, genetics, the immune system and to the environment. It might not be known right now how all of these tie together but they are all related and I’m certain with more research it’ll come together.
http://www.ncbi.nlm.nih.gov/pubmed/21967755
http://www.ncbi.nlm.nih.gov/pubmed/9358016
http://www.ncbi.nlm.nih.gov/pubmed/21367348
The immune system is a great angle of looking at the cause of schizophrenia and the role the complement system plays in its disease. Although the findings of the complement system and its C4 proteins provides evidence of schizophrenia, there are other angles to consider. The paper mentioned that this occurs in individuals in their late adolescence and early adulthood, so is this disease only in people who are healthy? Truth is no one knows the cause of schizophrenia and when it will happen. Yes, there are contributing factors such as environment and genetics, but why is the brain allowing synaptic pruning and it doesn’t happen to all young adults? The trend of hallucinating is seen in most drug addicts when they are high which stimulates different parts of the brain to shut down and see things much like schizophrenics. When drug addicts are sober why doesn’t the brain remain in that state of depression and goes through synaptic pruning? In some cases this does happen, but normally the brain is able to revert back to old functions and remain healthy. There are many questions concerning the brain and its function in regard to mental illness but there are no complete answers just assumptions
Synaptic pruning occurs in all individuals as it is a natural process that occurs during childhood development. In an attempt to answer your question, the brain is not simply allowing synaptic pruning to happen, but rather a gene variant facilitates synaptic pruning in schizophrenic individuals, as suggested by the study. The study suggests that excessive complement activity caused by a gene variant of C4 contributed to the onset of schizophrenia. Having taken abnormal psychology here as GSU, I know a little bit regarding hallucinations as symptoms that are present in both schizophrenic individuals and hallucination-inducing drug users. Drug addicts do not remain in a state of depression and thus synaptic pruning when sober because there is a lack of stimulus. Studies show substances such as MDMA, opioid, and even alcohol use has damaging, often irreversible effects on the brain. Delerium tremens is a result of alcohol withdrawal which is associated with the neurotransmitter GABA. Hallucinations from drug use occur due to the drug’s effect on the neurotransmitters serotonin, dopamine, and norepinephrine. These same neurotransmitters appear in differential levels when comparing a schizophrenic and healthy individual. An overactive hypothalamus-pituitary-adrenal (HPA) axis is seen as a biological factor that contribute to schizophrenia. An overactive HPA axis results in the chronic release of stress hormones that can ultimately damage areas of the brain that regulate memory formation and emotional responses. A gene variant, biological factor, and drug use may collectively or individually contribute to the onset of schizophrenia.
I came across a study that implicated an infectious component in Alzheimer’s disease (AD). This study suggested herpes simplex virus 1 (HSV-1)- among other microbial agents, may contribute to the onset of Alzheimer’s as HSV-1 can cause acute/latent infection resulting in immune-mediated damage to the brain. Features of AD include memory, personality, and cognitive defects that are a result of damage to the associated region of the CNS. Although the onset of AD is vastly different from schizophrenia, is it possible that schizophrenia may have an infectious component as well? The same areas of the brain are affected for both disorders, in addition to inflammatory component that is shared by both disorders. I think it is important to remember that schizophrenic individuals have a predisposition to the disease, but a variety of factors may contribute to the onset and severity of the disorder.
http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160152
http://jpet.aspetjournals.org/content/241/1/338.short
Before reading this blog post I didn’t really know and believe that there was a possible connection between mental illness and the immune system. The fact that the blog presented research showing possible evidence that a mental illness such as schizophrenia can be caused by an overly active complement system is surprising. It is already well known that the immune system can produce responses that are considered abnormal such as the attack of our own cells which can lead to autoimmune disorders. These autoimmune disorders can have physical repercussions on the victim. The fact that our immune system can not only affect us physical but mentally is revealing. There is a specific name for the study of the interaction between the immune system and psychological processes: Psychoneuroimmunology or PNI. Studies in this field have connected the immune system to another mental illness that is more common than schizophrenia: Depression. Researchers have linked inflammation as a possible determinant of common depressive symptoms such as avoidance and slow thinking. To be more specific, researchers have linked inflammatory messengers such as IL-1, IL-2 and IL-6 as well as cytokines with depression. The studies of this research have described that monocytes can express pro inflammatory genes that can lead to the secretion of cytokines. Inflammatory agents such as cytokines can relay information to the nervous system via the vagus nerve. The immune hubs of the brain are the microglia. These specialized cells (microglia) are activated during inflammation. These activated microglia have a enzyme called IDO that can direct tryptophan towards the production of quinolinic acid (NMDA agonist) which researchers believe are responsible for symptoms of depression. Exploring the possible connection of the immune system and mental health can provide new avenues for developing new treatments for people who suffer from mental illness such as schizophrenia and depression.
Source:
http://articles.mercola.com/sites/articles/archive/2014/04/17/psychoneuroimmunology-inflammation.aspx
In your blog post, you state that inflammation is a possible determinant of depression. Specifically, you mention that microglia respond to pro-inflammatory cytokines by secreting IDO which converts tryptophan into guinolinic acid, an NMDA agonist, ultimately causes symptoms seen in depression. It seems that treatment for such conditions could target the microglia cells and decrease their response to the pro-inflammatory cytokines. Well, in the research article “1,25-Dihydroxyvitamin D3 Facilitates M2 Polarization and Upregulates TLR10 Expression on Human Microglial Cells,” the authors explore the therapeutic effects of 1,25-dihydroxyvitamin D3, an active component in Vitamin D, on microglia inflammatory responses. The results of the paper suggest that the previously mention molecule does in fact exert anti-inflammatory action on microglial cells by facilitating M2 polarization, a process that alters the functional state of macrophages inducing tissue repair. Maybe the results of this research article has implication for the treatment of schizophrenia. It’s amazing what a little vitamin D can do for the body.
Verma R1, Kim JY.“1,25-Dihydroxyvitamin D3 Facilitates M2 Polarization and Upregulates TLR10 Expression on Human Microglial Cells.” Neuroimmunomodulation. 2016 Mar 22.
I really enjoyed the initial description of Schizophrenia by Mike Hedric. Having a primary, yet entertaining confession like that gave me a sense of realness for the disease. As the article states, Schizophrenia has mysterious causes and attention must be paid to the plural emphasis of origin. Researchers have done genomic wide assays, and there are so many genes that can be linked to schizophrenia, one single causative chromosome cannot be determined. However, changes to chromosome 6 have become a constant marker for schizophrenia and many other conditions. The supporting paper “Schizophrenia risk from complex variation of complement component 4” explains how excessive activity of the C4 protein within chromosome 6 is a point of interest, specifically the C4A portion. Similarly, another disease called transient neonatal diabetes mellitus (TNDM) is caused by over-activity of genes on chromosome 6 (1). In contrast to Schizophrenia, TNDM starts very early in life and improves with age. Even though the two diseases have pathological differences, they occur on the same chromosome. The mechanism of TNDM is known and could shine light on the various changes that cause schizophrenia. For example, TNDM occurs when the maternal gene of the baby is silenced, which amplifies or over-activates the paternal gene (2). Maybe a similar pathway is followed in schizophrenic patients which would make sense due to its high inheritability. A report on the full DNA sequence of chromosome 6 reiterates why such different conditions can come from the same gene. Chromosome 6 has the largest tRNA gene cluster of the genome and holds a significant amount of the immune system component, MHC (3). I think further research on how schizophrenia develops should be heavily aimed and experimented on with chromosome 6. Maybe with chromosome 6 concentrated research and developmental mechanisms of other diseases as blueprints, the little devil will eventually go away for schizophrenic patients.
1. https://ghr.nlm.nih.gov/chromosome/6
2. http://jonfwilkins.com/wp-content/uploads/2013/03/PMBTSv101_Wilkins_Ubeda.pdf
3. http://www.nature.com/nature/journal/v425/n6960/full/nature02055.html
This article was very interesting in that it connected the immune system with a complication of the brain in the central nervous system. This particular process causes Schizophrenia by the way of neuro inflammation caused by the complement system C4 gene. Based on the DNA sequence of the gene, the function changes. So within this research, there are two intertwining causes that lead to Schizophrenia; genetics and inflammation. But, why does these effects only occur during the adolescent and young adult stages of the person? Couldn’t these genetic mutations occur earlier in a child’s life? Professor Christos Pantelis explains in the video link below how the frontal lobe is the part of the brain greatly targeted by the mental disease. Unfortunately, the frontal lobe matures at the same time that the mental disease matures, during the young adult stage. So if there is a mutation of the C4 gene, affecting the amount of inflammation and function of the gene, then the frontal lobe is greatly affected. The frontal lobe is in control of the emotions, behaviors, higher functions, and personality. One answer to correcting the mutation of the C4 gene seems to be to stop and target it while children are at an early age, before the frontal lobe is fully developed. A lot more research must be completed in order to prevent the underlying causes of Schizophrenia.
Source: https://www.youtube.com/watch?v=iqoLO8HvC4s
I find it extremely interesting that many mechanisms and systems in our bodies are so sensitive to over-expression of genes as well as under-expression. This study suggests, with good evidence, that there is a correlation between C4A gene variants that express higher numbers of C4A proteins and schizophrenia. Specifically, schizophrenics tend to have higher expression of C4A proteins. Previous studies have found that C4A is a protein that is fairly important in mediating inflammation. The same previous studies have correlated lower C4A levels with certain autoimmune disorders. Specifically, we see that when C4A is under-expressed, the decreased regulation of local inflammation can cause systemic diseases such as systemic lupus erythematosus and insulin dependent diabetes mellitus. It seems to me that schizophrenia is the other side of the coin for C4A expression. As mentioned previously, while systemic lupus erythematosus and insulin dependent diabetes mellitus have been linked with under-expression of C4A, schizophrenia is linked with over-expression of C4A. The way I see it, a deficiency in C4A allows the immune system to run wild because there is one less factor in regulating it (C4A is missing or in numbers that are too low) resulting in autoimmune disorders; an excess in C4A results in C4A cleaving things that it would not normally cleave if it were present in normal numbers (in this case it starts cleaving proteins that are necessary for synapses to function) leading to a contributing factor to illnesses such as schizophrenia.
“Low C4 levels in Type 1 (insulin-dependent) diabetes”
http://link.springer.com/article/10.1007%2FBF00275752
“Low serum C4 concentrations: an inherited predisposition to insulin dependent diabetes?”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1547358/
Schizophrenia is a major psychological condition affecting hundreds of thousands of individuals worldwide, and is characterized cognitive impairments such as auditory hallucinations, decreased concentration, and delusional thinking. The onset of symptoms usually occur in late adolescents and early adulthood, and as the study (Schizophrenia risk from complex variation of complement component 4) suggests, is linked to an over activation of the complement system. The complement system is responsible for regulation of inflammation and elimination of infectious agents through activation of various proteins. In particular, this study has found a link between variations within the C4A gene that codes for the C4 protein of the complement. This gene variant leads to over activation of a process mediated by the complement system known as synaptic pruning, which ultimately leads to a decreased number of synapses within the brain, a characteristic trait seen in schizophrenic patients.
Many studies have reported a correlation in marijuana use and the development of schizophrenia. According to the article “Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders,” prolonged exposure to marijuana is associated with earlier onset and increased rate of the onset of psychosis. In another study (Marijuana use and brain immune mechanisms) THC was reported to inhibit the migratory capability of macrophage-like cells and suggests that early stage exposure to cannabinoids has potential to fundamental alter neuroimmune responses. Due to these findings, do you think it’s possible that cannaboid associated schizophrenia can be explained by a decrease in macrophage activity which could possibly increase the need for complement system response? As stated within the original article, an increase in complement system activity is linked to the development of schizophrenia.
Kelley ME1, Wan CR2, Broussard B3, Crisafio A4, Cristofaro S5, Johnson S5, Reed TA4, Amar P5, Kaslow NJ5, Walker EF6, Compton MT7.“Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset ofschizophrenia and related psychotic disorders.” Schizophr Res. 2016 Mar;171(1-3):62-7. doi: 10.1016/j.schres.2016.01.015. Epub 2016 Jan 17.
http://www.nature.com/nature/journal/v530/n7589/full/nature16549.html
Cabral GA1, Jamerson M2. “Marijuana use and brain immune mechanisms.” Int Rev Neurobiol. 2014;118:199-230. doi: 10.1016/B978-0-12-801284-0.00008-7.
http://www.sciencedirect.com/science/article/pii/B9780128012840000087