Immune-Brain Interactions

Question 1

What is the immune system considered to be?

Answer 1

The sixth sensory system

Question 2

What is the immune system?

Answer 2

Senses environmental change, co-ordinates a response including cellular, biochemical, physiological, psychological and behavioural changes, encodes a memory of the event for long term storage, self-regulates.

Physical substrate includes a range of cell types, working as a co-ordinated network with elements of centralised/hierarchical control, as well as distributed functionality.

Feedback and feedforward control elements.

Question 3

What are the three layers of immunity?

Answer 3

-Anatomical and physiological Barriers,
-Innate immunity
-Adaptive immunity (barrier is technically part of innate)

Immune system is about definding the body from pathogens and the effects of damage

Question 4

What is an example of anatomical and physiological barriers?

Answer 4

Skin
Ciliary cells in the lungs that clear debris
Low pH in stomach to destroy bugs

Question 5

What is the purpose of innate immunity?

Answer 5

A collection of cells and molecules which, with anything that’s not supposed to be there, they will engulf, break down, digest or immobolise, in order to stop those molecules interacting with your body in a negative way

Question 6

What is the purpose of adaptive immunity?

Answer 6

Different types of cells that are specialised, encoding a memory of a particualr pathogen and they will also break that pathogen down and one of the key ways they do that is to create antibodies that in the future then recognise that pathogen, attach themselves to it and that marks out that pathogen to be broken down with the same mechanisms that are part of innate immunity

Question 7

What is neuroimmunology?

Answer 7

Interaction of the immune and nervous systems
Nervous system control of immune system function

Immune responses within the nervous system

Question 8

What is psychoneuroimmunology?

Answer 8

Interaction between psychological processes, the immune and nervous systems

Definitions usually also include endocrine system (aka psychoendoneuroimmunology)
The “science of mind and body” ?

Question 9

What is the immune system regulated by?

Answer 9

CNS, PNS (autonomic) and endocrine-hormonal systems

Question 10

What was the CNS previously thought to be?

Answer 10

An ‘immune privileged’ site that it is protected from the often heavy handed immune system responses by the blood-brain barrier

But we now know this is an oversimplification

Question 11

What did Carson et al. (2009) find?

Answer 11

If people have organ transplants there are lots of issues such as rejection that occur because the immune system is picking it out as a response

But Carson found that:
-tissue ‘grafted’ into the CNS more able to survive than when implanted elsewhere- so there’s a strong down regulation of immune reacitivity in the CNS

-breakdown of BBB in disease characterised by infiltration of immune cells (helpful and unhelpful elements)

Question 12

Is there immunity within the brain?

Answer 12

Yes, its just a bit different and more specialised

Question 13

What is the brains own dedicated immune cell?

Answer 13

Microglia

Question 14

What do microglia do?

Answer 14

Processes reach out and look for signs of infection and then react

These can sense damage or infection and trigger larger scale immune reactions

They can react by calling up other cells e.g. astrocytes to help isolate that bit of damage from having effects more widely in the brain

Or they can communicate via the neurovascular unit (blood brain barrier) to the wider immune system and mount a more generalised responses

Question 15

What is the link between microglia and the cardiovascular system?

Answer 15

Close relationship with astrocytes whihc are heavily implicated in the vascular system e.g. endfeet wrap around blood vessels

Question 16

What did Brezzo et al. (2020) find?

Answer 16

Looked at systemic inflammation and how it may affect blood flow regulation in the brain

Injected mice with LPS (bit of the cell wall of a bacteria) - will be detected as infection but is not actually an infection

Injected systemically into the gut
What you get is a low level inflammation and immune response- body reponds as if there is infection within 1 day

In LPS groups compared to controls, there is increases in blood flow responses to whisker stims- dont understand this increase

Evidence that changes in neurovascular unit function occur rapidly in response to immune activation- there is an altered vascular response in the context of systemic inflmmation

Question 17

There is substantial evidence of how immune responses in the body are associated with what?

Answer 17

Altered function in a wide range of brain circuits

e.g. “Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression”
Felger et al. (2016)

-C-reactive protein (CRP) (downstream marker of levels of stress) is a circulating marker of systemic inflammation
- in this case inflammation levels are reducing the integrity of cortical networks that are related to reward

The question of causality remains somewhat unresolved although overall there is now good evidence that immune activation / inflammation may have a causative role in depression e.g. Lee & Giuliani (2019)

Question 18

What did Walker et al. (2020) find?

Answer 18

Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults

So immune responses (inflammation) also shown to be associated with changes in function within brain network underpinning cognition and in otherwise healthy individuals

As you increase inflammation, brain circuit integrity / connectivity is altered

But its hard to show what the immune responses in the brain itself were- is it due to inflammation chnages in the brain or due to neural input to the CNS associared with peripheral immune responses

Question 19

What is the general effect of inflammation in the periphery?

Answer 19

Sickness behaviour

Question 20

What is sickness behaviour?

Answer 20

A key component of generalized immune responses is the induction of ‘sickness behaviour’ - convalescence

These behaviours are adaptive and promotes recovery/recuperation

Question 21

What happens if we experience prolonged sickness behaviour?

Answer 21

Prolonged sickness behaviour can remodel normal behaviour and affect the brain circuits that might govern normal behaviour and this is why we think inflammation might be linked to things like depression, where sickness behaviours overlap with symptoms of depression and affective disorders in general

Question 22

What are pro-inflammatory cytokines?

Answer 22

Substances secreted by the immune cells – often for communication/regulation – can be pro- or anti-inflammatory

These go into all areas of the body and brain

Question 23

What does prolonged exposure to pro-inflammatroy cytokines cause?

Answer 23

Might lead to weight loss, changes in eating, changes in cardiovascular health, engagement in social situatuions, affect cognitive wellebing etc

Question 24

What did Couch et al. (2013) find?

Answer 24

showed LPS treatment modified BOLD pharmacological imaging responses in rat brain networks

These changes corresponded to reduced brain serotonin availability

This might partly underlie sickness behaviour

Question 25

What is Crouch et al.’s (2013) study evidence of?

Answer 25

Evidence that immune activation can modulate activity in the serotonin neurotransmitter system

We know that serotonergic function may be closely linked to depression and mood disorders (as well as normal affective function)

Evidence that inflammation alters the brain circuits linked to and heavily involved in depression and also showed a link to reduced availability of serotonin in the brain where SSRIs evidence the role of serotonin in depression

Question 26

What did Dantzer et al. (2008) find?

Answer 26

Transition from adaptive sickness behaviour to clinical depression dependent on existence of risk factors (may be genetic, altered neurotransmitter functionality, amplified immune reactions…)

Prolonged exposure to stressors (psychological or physical) may be an important source of these additional risk factors

Question 27

How does stress link to immune function?

Answer 27

If we have unresolved inflammation or stress situations then you end up with a feedback loop of elevated sympathetic nervous system activity- where the sympathetic nervious system is meant for short-term response not to help you cope with prolonged stress or inflammation

Stress, and the release of cortisol in particular, can suppress immune function (cortisol is anti-inflammatory)
Probably adaptive to prevent over-activation of immune responses to infection (a type of stressor)
But, when prolonged, can lead to quiet complex dysregulation of immune function
HPA and SNS activation are central to this