Please welcome this month's Scicurious Guest Writer, Phil Corlett!!

We often make a distinction between brains and brawn, between the mind and the body. But this mind/body dualism doesn’t actually exist. Instead, our bodies shape how our brains work, and vice versa. And the immune system could be an intersection between body and brain.

The brain and the immune system each have a sense of self: one for cognition, perception and action, the other to protect the body against infection. Each has to recognize what is and is not “their” body. If the mental sense of self is disturbed we might experience our actions as authored by another agent. If the immune sense of "self" is disturbed, our immune system might start to attack our body.

Early in the New Year, Leeds infirmary reported that they had performed the first hand transplant in the UK. This remarkable procedure involved grafting bones from the donor hand to the recipient arm, stitching together nervous tissue, connecting the circulatory systems and forging a physical connection between the hand and the recipient. The UK recipient, Mark Cahill, said: "When I look at it and move it, it just feels like my hand”. Not all patients have such a good outcome, for example, the recipient of the first hand transplant (performed in New Zealand) eventually requested that his new hand be removed. Even though it worked and his immune system did not reject the hand, the skin color did not match and it “felt like a dead man’s hand”. It seems that preventing the recipient’s immune system from rejecting the limb isn’t enough. We may also need a psychological connection to make a successful new hand.

We need to understand how this sense of self is created in order to respond when it is disturbed. Scientists explore our sense of self using an apparatus you might expect to find amongst a magician’s props rather than in a laboratory. Using a false rubber right hand, a screen and two paintbrushes, I can create a convincing illusion that the false hand is actually a part of your body.

First, I place your real right hand behind a screen. Then I place the rubber right hand on the other side of the screen in your field of view. Finally, I take the two paintbrushes and tickle the middle finger of your right hand and the rubber hand simultaneously. If you look at the rubber hand being tickled by the brush, it is likely that you will start to feel that the rubber hand belongs to you, that the distance between your hand and the rubber hand is shorter and, more objectively, if I threaten to stab the rubber hand, your real body will flinch(1). The rubber hand has become a part of your “self”.

The brain makes and uses a sense of self. So does the immune system. How do we know that these two systems communicate? Given that the rubber hand can be perceived as part of the self, does the immune system respond during the illusion? Histamine is an indicator of the activity of the innate immune system – the first line of defense that identifies infection sites, recruits immune cells to those sites (via chemical messengers called cytokines) and in humans activates its counterpart, the adaptive immune system, to engage a more long lasting immune response. According to classical immunology, the adaptive immune system can potentially perceive anything that is not itself. It has a vast repertoire of antibodies, and it triggers the destruction of anything that it actually perceives. This perception involves the binding of antibodies to small proteins on foreign bodies called antigens. Antigens are recognized as not self and attacked. So how does the immune system respond during the rubber hand illusion? Is it more active? Does it target the real hand since the rubber hand is now a part of the self?

Nadia Barnsley, Lorimer Moseley and their colleagues from Neuroscience Research Australia measured the immune response in the real body part, the one replaced by the rubber hand(2). First, they induced the rubber hand illusion. Then, they pricked the skin and applied histamine on the arm subject to the illusion and the other arm (as a control site). Histamine induces the Triple Response of Lewis, an initial red line on the skin, followed by a flare around the line and then finally a weal on the skin. So if you prick the skin in the presence of histamine, the weal will be larger. It appears that the illusion increased the histamine response in the real limb; because the weals were larger in that arm compared to the control arm and the size of the weals were correlated with how vividly the subjects experienced the illusion. The illusion caused subjects to mount an innate immune system response to their own arm. And this suggests that if the brain’s representation of the body changes, our immune systems will react as well, reflecting the new sense of “self”.

Some patients with schizophrenia (a serious mental illness characterized by hallucinations and delusions; perceptions and beliefs that other people do not share) sometimes lack what we call a sense of “self agency”. Their actions feel like they are under the control of some malevolent external force: 'when I reach my hand for the comb it is my hand and arm which move, and my fingers pick up the pen, but I don't control them (...) I am just a puppet who is manipulated by cosmic strings’ (3).

So if some people with schizophrenia have issues with cognitive sense of self, could they also have a problem with the immune sense of “self”? It turns out they can. Autoimmune disruptions in patients with schizophrenia were first reported in 1937(4). Autoimmunity happens when the immune system fails to discriminate self from other and mistakenly “attacks” the self. When we think of autoimmune disorders, we usually think of diseases like lupus, but there is evidence that autoimmune disorders can also cause delusions, the bizarre and fixed false beliefs that characterize schizophrenia. For example, Morvan’s syndrome , in which patients mount an immune response to their own neurotransmitter receptors, can also suffer from delusions. One patient with Morvan’s developed paranoid ideas about the medical team treating him, his family members and the hospital where he was being treated, believing falsely that they were trying to involve him in a drug smuggling ring. This patient was treated with plasma exchange, a blood purification procedure in which his blood cells were separated from the plasma and the cells retuned to his circulation diluted with fresh plasma(5). Plasma exchange removed the autoantibodies from his blood, allowing his neurotransmitter receptors to return, and his delusions resolved immediately and permanently.

In another case of Morvan’s, the patient reported reduplicative paramnesia; he firmly believed that his home had been copied by a stranger and that the replica existed 40 miles away. Every detail of the replica including ornaments and personal effects had been copied exactly. He even stated that his wife had visited the replica. This time treatment with immunoglobulin caused the delusion to resolve6. Immunoglobulin is a specific antibody derived from blood donors. We do not know the definitive mechanism of immunoglobulin treatment but it seems to encourage the removal of autoantibodies by binding to them and it may also have anti-inflammatory effects involving histamine. Again, calming the immune response reduced the delusion.

So delusion like-ideas – “that rubber hand belongs to my body" – can change the immune system and, in turn, changes to the immune system – such as Morvan’s - can cause delusions.

Much of what we perceive and believe is driven by our past experiences. This is why we are tricked by optical illusions, because our expectations shape what we perceive, and get it wrong. We see a rotating mask, for example, and we get the uncanny sensation that the mask continually faces outwards (the hollow-mask illusion), because in our lifelong experience with faces, they almost always point outwards. We see what we expect to and so we are fooled by illusions.

Delusions might be a more serious example. Patients with delusions might see and believe things about the world that others don’t because the expectations that their brains have formed and use are very different from those of people with out delusions. Those expectations partly form in because of the spontaneous nerve cell activity in cortex (7), shaping the way the brain responds to real sensory stimulation. Sensory stimulation in turn sculpts and changes future expectation. Expectations drive perceptual illusions. Delusions might also be driven by maladaptive and noisy expectations about the world. Is there anything like an expectation in the functioning of the immune system?

Immunologists certainly rely on cognitive metaphors in their work: perception and recognition, learning and memory, and self vs. non-self(8). But does the immune system expect or predict?

Franciso Varela suggested that we think of the immune system as a network of interacting lymphocytes (the cells that produce antibodies). The survival of a lymphocyte, its proliferation and its capacity to secrete antibodies depends on its network of interactions with other antibodies. If a lymphocyte has too few interactions it ‘dies of loneliness’(9); too many and it ‘dies of suffocation’9. The lymphocytes create the network, in the form of their antibodies’ recognition of and interactions with the receptors of newly emerging lymphocytes. And the antibodies are produced as a consequence of these very interactions. Hence the network determines itself and its maintenance(8).

According to Varela, the immune system recognizes and protects itself by dividing into two complimentary compartments: the central immune system (CIS) and the peripheral immune system (PIS). The CIS is composed of natural antibodies found in the sera of all vertebrates even when they are secluded from all contact with the environment. These natural antibodies are produced spontaneously and appear to be the result of the internal activity of the immune system. They are produced by internally activated lymphocytes that represent 10% of the total lymphocyte number. The remaining 90% of lymphocytes are inactive and do not secrete antibodies. They have no effective network interactions and represent the PIS. PIS cells that retain a minimal interaction with the network are maintained and are responsible for mounting an immune response to novel pathogens the body encounters. So the CIS is the “self” and the PIS helps recognize “non-self”, by being drawn into the antibody expressing network8. The immune system expects and predicts itself, the CIS. When something violates that expectation, like an invading infection, the immune system responds by drawing lymphocytes into the network from the PIS that can respond to the invasion.

The cells that the central immune system generates spontaneously (the CIS) are rather like the spontaneously active nerve cells in the cortex(7), that spontaneous activity actually represents expectation about upcoming stimuli(7). Although they appear to be noise, the actions of these cells are constantly tuning the dynamics of the networks they are embedded in to respond efficiently, perhaps to distinguish self from non-self or expected stimulation from unexpected.

About of patients with schizophrenia treated with antipsychotic drugs continue to experience a very disturbed sense of self. Perhaps some of them are actually suffering from autoimmune illnesses and they might instead benefit from plasma exchange or immunoglobulin treatment. This is a new avenue of research for cognitive science, immune biology and clinical psychiatry. They all have a lot to learn from one another, not least how a rubber hand, paintbrush and a pin-prick might yet inspire a new understanding of delusional beliefs.

1 Ehrsson, H. H., Wiech, K., Weiskopf, N., Dolan, R. J. & Passingham, R. E. Threatening a rubber hand that you feel is yours elicits a cortical anxiety response. Proceedings of the National Academy of Sciences of the United States of America 104, 9828-9833, doi:10.1073/pnas.0610011104 (2007).

2 Barnsley, N. et al. The rubber hand illusion increases histamine reactivity in the real arm. Curr Biol 21, R945-946, doi:10.1016/j.cub.2011.10.039 (2011).

3 Mellor, C. S. First rank symptoms of schizophrenia. I. The frequnncy in schizophrenics on admission to hospital. II. Differences between individual first rank symptoms. Br J Psychiatry 117, 15-23 (1970).

4 Lehman-Facius, H. Uber die Liquordiagnose der Schizophrenien. Klin Wochenschr 16, 1646-1648 (1937).

5 Parthasarathi, U. D. et al. Psychiatric presentation of voltage-gated potassium channel antibody-associated encephalopathy. Case report. Br J Psychiatry 189, 182-183 (2006).

6 Hudson, L. A. et al. Reduplicative paramnesia in Morvan's syndrome. J Neurol Sci 267, 154-157 (2008).

7 Berkes, P., Orban, G., Lengyel, M. & Fiser, J. Spontaneous cortical activity reveals hallmarks of an optimal internal model of the environment. Science 331, 83-87, doi:10.1126/science.1195870 (2011).

8 Stewart, J. & Coutinho, A. The affirmation of self: a new perspective on the immune system. Artif Life 10, 261-276, doi:10.1162/1064546041255593 (2004).

9 Vaz, N. M. & Varela, F. J. Self and non-sense: an organism-centered approach to immunology. Med Hypotheses 4, 231-267 (1978).

Dr Phil Corlett is an Assistant Professor of Psychiatry at Yale. He completed his PhD in Cognitive Neuroscience at Cambridge where he worked with Paul Fletcher and Trevor Robbins in the Brain Mapping Unit. Since moving to the US in 2009 he has expanded his research program to explore addiction and alcoholism in terms of habit formation. He is interested in delusions and in using brain data to learn about belief. He is a regular contributor to F1000 and a newcomer to Twitter (@PhilCorlett1).