Introduction to Neuroinflammatory Disorders

00:01 In this talk, we're going to review neuroinflammatory disorders.

00:05 And we'll begin with an introduction to neuroinflammatory disorders.

00:10 To begin, let's talk about the pathophysiology.

00:13 What's going on when there's an immune attack in the brain or central nervous system? Well, we start with the brain.

00:20 And in the brain lives, the neurons.

00:22 The neurons are protected from the immune system by the blood–brain barrier.

00:26 What we see here is a schematic showing the neurons in the brain, a blood vessel and the blood-brain barrier.

00:33 The immune system is composed as we know of T cells, B cells, and natural killer cells and those are maintained within the blood vessels and separated from the central nervous system by the blood-brain barrier.

00:45 The blood-brain barrier is made up of astrocytes.

00:48 Astrocytes form a thick and protective wall between the blood vessels in the brain and prevent immune cells from infiltrating into the central nervous system.

00:59 In the central nervous system, the primary immune cell in the immune compartment are the microglia.

01:05 And they're the resident immune mediators that function as immune regulators.

01:11 And also pericytes.

01:13 Pericytes are immune cells located around the periphery of the blood vessels, primarily around meningeal blood vessels and serve an immune function.

01:22 In autoimmune conditions, what we see is that there's infiltration of that systemic immune response, the T cells, the B cells, the natural killer cells, or some combination of the three into the brain through the blood-brain barrier, resulting in damage to the nerve, to the myelin, to the axon, or some aspect of the central nervous system.

01:44 When I think about autoimmune conditions in the central nervous system, there's five key mechanisms.

01:49 And I want you to understand and at least appreciate some of the things that happen that cause CNS autoimmunity.

01:56 The first thing we'll talk about is molecular mimicry.

01:59 Where an antigen on a virus mimics an antigen in the brain.

02:03 And as a result of the immune response to the virus, we see an attack in the brain.

02:08 The second cause or underlying pathophysiology of CNS autoimmunity are sequestered proteins.

02:15 And we'll talk about how proteins are normally sequestered from the immune system as a result of an infection, they can be released.

02:21 and this results in an immune attack in the central nervous system.

02:26 I want you to know about the bystander activation or altered regulation, where as a result of some infectious process.

02:32 There's activation of cytokines which revs up the immune system and can result in a CNS attack.

02:39 We'll also talk about an abnormal host development and normally, the thymus is involved in creating B cells and T cells that attack foreign antigens and are not auto reactive.

02:51 And in some circumstances, the body can generate autoreactive immunity that can result in CNS immune attacks.

02:59 And then the last thing is we'll talk about paraneoplastic causes of CNS autoimmunity.

03:03 And I want you to understand each of these five, underlying pathophysiologic processes that contribute to neuroinflammatory disorders.

03:13 First, let's talk about molecular mimicry.

03:15 So here we're looking at a schematic of a neuron, the blood-brain barrier, and the blood vessel as well as a new virus that is expressing an antigen.

03:25 In the setting of molecular mimicry, the immune system responds to the virus, which is normal.

03:29 That's what you want the body to do to attack the virus and clear it.

03:33 But in this case, the virus is expressing an antigen that's also expressed in the brain.

03:39 And so in some circumstances, there is a hyperactive immune response to that antigen to kill the virus, but this also results in attacking of that same antigen in the brain and that contributes to the development of a neuroinflammatory disorder or CNS autoimmunity.

03:57 This is the first type of CNS autoimmunity.

04:01 The first cause, underlying cause, of a neuroinflammatory disorder.

04:06 What about sequestered proteins? How does this work? Well, again, we have our same neurons which are expressing an antigen protected from the systemic circulation by the blood-brain barrier.

04:16 Here some infectious process results in release of an intracellular antigen that was previously not seen by the immune system.

04:25 So here you can see in this schematic infection with a virus can result in release of those intracellular proteins.

04:32 Normally, the body's immune system should attack that antigen recognizing it as unfamiliar.

04:38 But in this case, the antigen is also contained within the neurons.

04:42 As a result of a hyperactive immune response, we see infiltration of that systemic inflammatory response into the brain and this can contribute to the development of CNS autoimmunity or a neuroinflammatory disorder.

04:57 What about bystander activation? How does that work? Well, again, we have the neurons in the brain separated from the systemic circulation by the blood-brain barrier.

05:05 Here as a result of some process that irritates activates cells, we have release of cytokines due to an infectious process.

05:13 Those cytokines rev up the immune system, the immune system is able to infiltrate into the brain and that sets off this CNS autoimmune attack.

05:22 So this is another underlying cause for the development of a neuroinflammatory disorder.

05:28 What about abnormal host development? How does that work? Normally, the thymus is the organ in the body that results in development of B and T cells, normal immune cells that respond to foreign antigens and destroy potentially autoreactive antibodies, and immune cells.

05:49 In some circumstances of abnormal development, the body fails to degenerate, discard, and destroy those autoreactive immune effector cells.

06:00 And as a result, they're able to identify antigens such as those on neurons infiltrate into the brain and result in the development of CNS autoimmune conditions.

06:11 And then the last underlying process that can contribute to CNS autoimmunity is a paraneoplastic process.

06:18 Here, patients may develop a tumor.

06:19 In fact, we're all really developing tumors at all times throughout our lifetime.

06:24 And the normal process for is for the body's immune system to recognize that tumor, to see it as abnormal and to kill and destroy it.

06:32 In some circumstances, that antigen that is contained on the tumor is also present on the surface or inside of nerves.

06:40 The body's immune system is revved up as a result of that cancer.

06:43 And when the immune system can infiltrate into the brain, we have the development of a paraneoplastic neurologic disorder.

06:51 In many cases, the neurologic disorder can precede the development or recognition of the cancer.

06:56 The body's immune system is doing a good job at keeping the cancer at bay, but we see this neurologic syndrome that develops and really should herald additional workup for an underlying cancer.

07:08 And so these five causes or underlying pathophysiologic mechanisms are the mechanisms by which CNS autoimmunity can develop.