Autoimmunity

00:00 Hello and welcome.

00:02 We're going to finish up our discussion of immune mediated injury by looking at autoimmunity and other forms of immune damage.

00:11 So autoimmunity to begin with, this is where we lose tolerance to self.

00:15 How does that happen? Well, there are probably susceptibility genes you may have in some circumstances.

00:21 A cell that makes too much cytokines or responds to well to particular cytokine stimulation through a receptor polymorphism, you may have a MHC molecule that can bind up particular peptides that someone else doesn't.

00:36 So you have a susceptibility.

00:39 Important that you do not think that that makes you guaranteed to have autoimmune disease.

00:45 In fact, the susceptibility gene just allows you to develop autoreactive lymphocytes or self reactive lymphocytes.

00:53 So for some reason, you don't delete that autoreactive clone.

00:57 Interestingly enough, most of the people walking around, probably have T cells that recognise myelin.

01:05 "What?" You're saying.

01:06 Well, yeah, those are just out in the periphery, though.

01:09 They never really get to set up shop in the brain.

01:11 But you can find in most people a low level of T cells responding to myelin, that could potentially cause multiple sclerosis.

01:20 Okay, regardless of how that actually happens, susceptibility genes allows us to develop these self reactive lymphocytes.

01:29 And they're out there circulating, they are interacting with antigen presenting cells.

01:32 And in the absence of a lot of self antigen from injury or whatever, in the absence of that self antigen, you don't have much activation.

01:41 But if you get local damage, secondary trauma, due to infection due to ischemia, due to any of a variety of injuries, then you will have more local antigen elaborated, you will have greater antigen presentation to T cells, you'll get a clonal T cell expansion.

01:59 And now those T cells through DTH through, cytotoxic T cells, through the production of antibodies, will now cause substantial tissue injury.

02:08 So that's where autoimmunity comes from.

02:12 A good example of this is type 1 diabetes.

02:15 The major underlying mechanism, if we're putting in the type 1, type 2, type 3, type 4 categories, is that this is type 4, delayed type hypersensitivity disease.

02:26 And basically you have an initial loss of self tolerance, those cells are out there, they're circulating.

02:32 And it may be a particular major histocompatibility linkage, as they say it could be receptor expression or receptor activation, just failure to get rid of that autoreactive clone.

02:46 Interestingly enough, if we look at the incidence of diabetes mellitus, type 1 Diabetes mellitus, and MHC identical siblings.

02:55 So it should have similar antigen repertoires, similar ability to respond to antigens, we only find a 12% concordance of type 1.

03:07 And interestingly, even genetically identical twins, siblings, there's only a 36% chance of concordance.

03:15 Meaning that both twins will have type one diabetes.

03:19 This just emphasizes that really important point.

03:22 That it's not just about genetic susceptibility.

03:24 Secondary effects, secondary events such as injury, or toxins, trauma, infections, whatever, are the triggering event that will then drive the final disease.

03:36 So what happens in diabetes mellitus type 1? So this is shown here, the upper panel, on the right hand side shows you normal islets.

03:44 On the lower hand panel, on the right hand side, there is increased mononuclear cell infiltrate in this patient who will go on to develop loss of the beta cells and a type 1 diabetes.

03:57 That injury that's happening there, the lymphocyte and macrophage insulitis, inflammation of the islets is causing a DTH type response.

04:08 There are also cytotoxic T lymphocytes, so we're getting direct cell killing, and we're getting secondary effects due to the elaboration of cytokines and the recruitment of macrophages and other inflammatory cells.

04:22 Again, because the T cells are being activated, those helper T cells are making appropriate cytokines to drive B cell proliferation and the generation of auto antibodies.

04:31 So we can find a number of circulating antibodies that recognise antigens normally present within the islet.

04:39 These auto antibodies are not felt to be causal.

04:42 So they are not the reason that we're getting damaged.

04:45 They're a secondary effect of having activated T cells, of having activated helper CD8+ lymphocytes.

04:54 And the development of those auto antibodies, in many cases, will proceed symptomatology and they do correlate with progression.

05:00 But it can or not felt to be causal.

05:03 So that's just an example of autoimmunity and there are other examples.

05:06 So inflammatory bowel disease, multiple sclerosis, scleroderma, Myathenia gravis, those are all autoimmune diseases and again, predictable consequences of activating the immune response to self antigens.