Comments on: Autoimmunity and CD1 (Part II) http://www.iayork.com/MysteryRays/2008/05/18/autoimmunity-and-cd1-part-ii/ Meddling with things mankind is not meant to understand. Also, pictures of my kids Sat, 25 Jun 2011 18:45:54 +0000 hourly 1 http://wordpress.org/?v=3.3 By: iayork http://www.iayork.com/MysteryRays/2008/05/18/autoimmunity-and-cd1-part-ii/comment-page-1/#comment-5398 iayork Wed, 28 May 2008 01:53:24 +0000 http://www.iayork.com/MysteryRays/?p=146#comment-5398 Kay, I don't know either, and I think that it's an open problem. In fact the whole mechanism is mostly hypothetical; as I say this is one of the few cases where even this many steps have been tracked through. My own guess, belief, understanding, whatever you want to call it, is that there are quantitative differences in the stimulation, and qualitative differences in the antigen, that account for the pathogen requirement. On the one hand most tissue damage that doesn't involve infectious agents is transient; even if there is large-scale tissue damage it's over in a short period (crush injuries, toxins) and then the inflammation starts to get cleared up. Pathogens are around longer, amplify their signal instead of attenuating it, and probably have a wider variety of signals. (I can think of exceptions to all of these, though.) I would also suspect that pure self antigen is at least partially tolerized, whereas a microbial antigen that's only partially similar might have only partial tolerance. For example, a single CTL epitope that partially cross-reacts, but that isn't linked to CD4 epitopes for TRegs to see, might be more dangerous than a full-length self protein with suppressive epitopes linked to the activating ones. (In fact, thinking about it more, that seems to be a likely method of breaking tolerance.) But at the end of the day (as always) "more research is needed" ... which is one reason I'm submitting my autoimmunity grant application tomorrow. Kay, I don’t know either, and I think that it’s an open problem. In fact the whole mechanism is mostly hypothetical; as I say this is one of the few cases where even this many steps have been tracked through.

My own guess, belief, understanding, whatever you want to call it, is that there are quantitative differences in the stimulation, and qualitative differences in the antigen, that account for the pathogen requirement.

On the one hand most tissue damage that doesn’t involve infectious agents is transient; even if there is large-scale tissue damage it’s over in a short period (crush injuries, toxins) and then the inflammation starts to get cleared up. Pathogens are around longer, amplify their signal instead of attenuating it, and probably have a wider variety of signals. (I can think of exceptions to all of these, though.)

I would also suspect that pure self antigen is at least partially tolerized, whereas a microbial antigen that’s only partially similar might have only partial tolerance. For example, a single CTL epitope that partially cross-reacts, but that isn’t linked to CD4 epitopes for TRegs to see, might be more dangerous than a full-length self protein with suppressive epitopes linked to the activating ones. (In fact, thinking about it more, that seems to be a likely method of breaking tolerance.)

But at the end of the day (as always) “more research is needed” … which is one reason I’m submitting my autoimmunity grant application tomorrow.

]]> By: kay http://www.iayork.com/MysteryRays/2008/05/18/autoimmunity-and-cd1-part-ii/comment-page-1/#comment-5382 kay Mon, 26 May 2008 15:13:09 +0000 http://www.iayork.com/MysteryRays/?p=146#comment-5382 Something I never quite understood about autoimmunity is why we need microbial antigens that mimic a host antigen, in addition to a danger signal. Shouldn't any necrotic cell death, together with an inflammation, suffice? During necrosis, a lot of cellular components leak out, which are normally hidden from B-cells and could elicit an immune response. Apparently, this is not the case. Is this because of a previous 'physiological leakage' in the absence of a danger signal, making the immune system get used to intracellular antigens? Something I never quite understood about autoimmunity is why we need microbial antigens that mimic a host antigen, in addition to a danger signal. Shouldn’t any necrotic cell death, together with an inflammation, suffice? During necrosis, a lot of cellular components leak out, which are normally hidden from B-cells and could elicit an immune response. Apparently, this is not the case. Is this because of a previous ‘physiological leakage’ in the absence of a danger signal, making the immune system get used to intracellular antigens?

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