Immunity and the Brain by whyking

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									Stanford Microbiology and Immunology: Innate Immunology M&I 104/204
Immunity and the Brain, David Schneider, Spring 2005
Why is the brain ignored as an immune organ?
       College level immunology texts do not discuss fever, steroids or sickness
       behavior.
       Feeling and acting sick are behaviors mediated by the brain. When you come
       down with the flu you don’t say, “ Hmm, my dendritic cells have detected a
       foreign PAMP and are now activating my T cells. Soon I will be making
       antibodies.” Instead you say, “I feel like crap. I’m going to bed.”

The brain receives immune signals and coordinates responses.
       These responses include:     steroid release
                                    Fever
                                    Sickness behaviors
                                    Neural anti-inflammatory signals

There are two major problems to discuss when dealing with the brain as an immune
organ – how do messages get in and how do messages get out?

       Brain is protected by BBB –blood brain barrier
               Tight junctions in endothelium
                       Induced by astrocytes in close contact with endothelium
               Large, charged molecules do not pass the endothelium
               Only very small and lipophilic molecules may pass.
               Molecules like TNF, IL1, IL6 are largely excluded

       4 methods discussed for entry into the brain.
              1. Leaky blood brain barrier
                     Some portions of the BBB are porous
                     Around the pituitary
                              i. Required for release of hormones
                     Vomit center
                                    area postrema
                                    recognition of vomit inducing compounds in the
                                    blood.
                     OVLT – organum vasculosum laminaie terminalis
                             Anteroventral wall of the third ventricle
                             Signals proposed to diffuse to the temperature center
                             (POAH – see below)
              Active transport across the endothelium
                     Signaling molecules can be transcytosed at some measurable rate
                     across the BBB
                     Levels of cytokines are apparently not high enough in the brain to
                     account for the speed and intensity of the fever response


              Second messengers




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Stanford Microbiology and Immunology: Innate Immunology M&I 104/204
Immunity and the Brain, David Schneider, Spring 2005
                    Endothelial cells can receive signals respond by producing
                    prostaglandins or nitric oxide

             Neural signaling
                    After all, we are talking about the brain.
                    The vagus nerve relays immunity related signals to the brain.

             This is an area of flux and debate. Results appear to vary on the precise
             details of the model used. Doses of stimulants are very important.

             I will concentrate on the role of the vagus nerve in transmitting a signal to
             the brain but there are certainly other factors at play.

             What is the vagus nerve?
                    Contains afferent and efferent neural processes.
                    Innervates the heart, liver, intestine
                    Intraperitoneal injection of LPS in a rat leads a response
                            Do not get the response if the nerve has been cut
                    Air pocket models
                            Introduce LPS into a subcutaneous air pocket.
                            Anaesthetics can block a response to LPS as well as cutting
                            the nerve

             What are some of the gross responses of the brain
                   Fever
                          Regulated by hypothalamus
                                          Homeostasis and behavioral drives
                                                  Fight or flight
                                                  Thermoregulation
                                                  Osmolarity: thirst
                                                  Satiety and feeding centers
                                  Distributed regulation
                                  No single lesion alters temperature control
                                  The POAH – preoptic anterior hypothalamus is
                                  associated with thermoregulation as heating and
                                  cooling this are has large effects.

                            We can develop fevers in most ambient temperatures
                                  Fever is a different physiological state from
                                  excessive heating due to exercise.
                                          Following forced cooling of the body during
                                          exercise the body returns to 37°C
                                          Following forced cooling of a febrile patient,
                                          the temperature rises to fever levels again.

                    How is temperature regulated?



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Stanford Microbiology and Immunology: Innate Immunology M&I 104/204
Immunity and the Brain, David Schneider, Spring 2005
                          Balance of heat generation and heat loss
                                 Heat generation
                                        Metabolic
                                        Shivering
                                 Heat loss
                                        Sweating
                                        Heat seeking behaviors
                                        Vasoconstriction at periphery

                          Maybe you can get a better picture looking at poikilotherms
                                Lizards generate fevers by behavioral means
                                They do not shiver or sweat
                                Lizards instead bask, rotate their bodies with respect
                                to the sun and change their body shapes
                                Seek warmer temperatures when injected with
                                elicitor

                                 Fish will also alter their body temperatures in
                                 response to an immune challenge
                                        Infected fish warm their bodies by 3°C
                                        By swimming to a warmer area in the pond

                                 Insects also thermoregulate in response to a fever
                                         Locusts and crickets will move to warmer
                                         Immune challenged
                                         But is this the only type of temperature
                                         modulation they can perform?
                                                 Bumblebees can shiver (actually they
                                                 don’t shake – they are better at it
                                                 than we are)
                                                 This can raise their thorax
                                                 temperatures 30°C for flight
                                                 I don’t think anyone has checked to
                                                 see if they can run a fever in this
                                                 manner…

                          What are the mediators of the fever response –
                                Aspirin blocks the response in all of these animals
                                        -suggesting that prostaglandins play a role in
                                        signaling

                   Current models
                          TNF induces IL-1
                          IL-1 induces IL-6
                                 IL-6 mutant mice do not generate fevers in response
                                 to IL-1 injection



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Stanford Microbiology and Immunology: Innate Immunology M&I 104/204
Immunity and the Brain, David Schneider, Spring 2005
                              IL6- acts on vagus nerve – ultimately sending signals back
                              to the hypothalmus
                              Results in release of prostaglandins in the brain

                      But how does all of this result in changes in temperature regulation?
                            Model
                                    Prostaglandins act by resting the body’s thermostat
                                    Warm and cold sensitive neurons
                                    Warm sensitive are inherently thermosensitive and
                                    fire maximally at 37°C
                                    Warm sensitive output inhibit cold sensitive
                                    neurons
                                    Inhibition of warm sensitive neurons results in
                                    firing of cold sensitive neurons and an increase in
                                    body temperature

                      Is fever good or bad?
                              Allow fever – increased survival in some cases
                                     Lizards allowed to thermoregulate had higher
                                     survival than those kept at a lower temperature
                              Block fever – increased death

                              When we treat fever – drugs also treat sickness behavior
                              and pain.
                                     – we feel better when we take NSAIDS but not
                                     necessarily because we have reduced the fever.

                      Why might fever be good?
                           No clean explanation yet
                           Suggestions that neutrophils work better at high
                           temperatures.

                      Hypothalamus – pituitary- adrenal axis
                            Cascading release of hormones results in release of steroid
                            hormones from the adrenal organs - cortisol
                            Known for some time these inhibit inflammation
                                    -used as drugs and anti-inflammatories
                            Response occurs over long time period – greater than hours
                            to release circulating compounds
                            These act systemically to reduce inflammation


Avoid some confusion – just because a molecule was discovered as an interleukin or a
neuropeptide does not mean that is the sole role for it in the body. Some confusion arises
when organs simply reuse a perfectly good signaling molecule. The following section
tries to avoid those discussions and looks directly at neuron-macrophage signaling



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Stanford Microbiology and Immunology: Innate Immunology M&I 104/204
Immunity and the Brain, David Schneider, Spring 2005


                   Direct neural signaling – cholinergic anti-inflammatory pathway
                           Back to the vagus nerve
                           Cut it in inflammation models and inflammation runs out of
                           control
                                   Inject LPS into rats
                                   Stimulate vagus nerve
                                   No TNF release – increased survival of ratsNo-
                                   anti-inflammatory signal is provided
                                   Severing nerve – no inhibition and sensitization to
                                   LPS
                           Macrophages can respond to signals produced by neurons
                                   Direct response to molecules normally considered
                                   to be neural signals – norepinephrine, acetylcholine
                                   Receptor of macrophage is a7 pentamer
                                   Stimulate nerves of a7 mutant mice – no protection
                           This receptor is nicotine sensitive
                                   Nicotine is immunosuppressive
                                   Can protect against inflammatory disease
                                   Ulcerative colitis
                                   Reduces fever with influenza

                          Acupuncture? Hypnotism?




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