Through negative selection of T-cell in the thymus T-cells lose the possibility to react to antigens which are "body own" -> self antigens. Though there are more than just this negative selection for preventing T-cells recognizing own antigens some T-cell become self reacting. This T-cell in our case cd4 T-cells can recognize antigens presented on MHC II complexes by APC cells.

And the question is:

Who presents the self-antigens to the wrong selected CD4 T-cell, which leads to autoimmunity? How does the APC cell get this self-antigen in the first place?

  • $\begingroup$ Welcome Croin! Please add a little bit of detail to this question. Tell us a few sentences explaining the facts you are presenting, then ask the question about those facts. For example: In autoimmunity, a theory is that the wrong CD4 T cells...." etc and provide a reference so the person answering the question can look into your source of info for more insight. That makes the question richer and you will get better answers! $\endgroup$ – DoctorWhom Aug 12 '17 at 8:18
  • $\begingroup$ Hi, thank you for taking time giving me a better insight. But the question is pretty straight forward there is no need for further details. Either a person knows the stuff or doesn't. The question is like "Hello world" for immunology - autoimmune diseases". $\endgroup$ – Croin Aug 12 '17 at 10:02
  • $\begingroup$ I get your point, but I'm advising you on SE guidelines for higher quality questions. This isn't like every other Q&A site. Asking a question isn't just for you, it's contributing to building a body of knowledge. Also without a little more info, your question sounds like a quiz or homework question otherwise. $\endgroup$ – DoctorWhom Aug 12 '17 at 10:14
  • $\begingroup$ Actually I am going to vote moving this to BiologySE. There is a fine line between Health and Bio on physiology/pathophysiology topics, and I think there are more molecular/cellular science specialists on the Bio side, and more clinical-/pathology oriented specialists on this side. I would love if we had more people straddling both sites, as I think more discussion of difficult concepts in physiology would really enrich this site! $\endgroup$ – DoctorWhom Aug 12 '17 at 10:17
  • $\begingroup$ I do think the underlying question about the mechanism is good. I don't remember enough from immuno in school to answer off the top of my head. I gave you that advice because looking at it, I know that there are thought to be multiple mechanisms of autoimmunity, and you state that like it's the only one. Hence the recommendation to provide a better description in the question body. I upvoted your question because it is a quality topic that I'd like to see be discussed, but gave you advice how to improve the quality of the question itself. $\endgroup$ – DoctorWhom Aug 12 '17 at 10:20

Since you already know that the repertoire of T cell receptors is developed in the thymus, the missing half of the story in the context of antigen-presenting cells is that MHC complexes do not discriminate between self, foreign and mutated self peptides. The take home point is that selection in the thymus is meant to produce a repertoire of T cells which can overcome this fact.

In all healthy tissues, nucleated cells express class I MHC molecules loaded with self-peptides. A T cell probably isn't going to respond to it, however, because trafficking of T cells into tissues requires signals such as cytokines and chemokines. The T cells circulate to and from the lymph node T cell zones.

In the context of inflammation and cellular injury, self proteins may be released into the extracellular space where they're regularly cleared by macrophages via endocytosis. The extrinsic antigen presentation pathway loads peptides onto class II MHC molecules. In this very context, T cells are trafficked into distressed tissues by activated endothelium, where they interact with tissue APCs. Autoreactive clones that escaped thymic selection have the opportunity, then, to react to self antigens, ignoring regulatory or suppressor cells (ref).

Not just self-peptides, however, but also potential self-antigen mimics that take well meaning T cells directed against bacterial peptides, which happen to closely resemble a self antigen, and pit them against your own tissues (example). Unlike autoimmune T cells that have escaped selection and attack your cells, this invites T cells that have gone through the proper channels to do so as well.

See Cellular and Molecular Immunology, 8th ed. for an even better overview of T cell-based autoimmunity.

  • $\begingroup$ So basically it goes like: Injury -> self antigen in extracellular space -> Uptaken by Macrophages -> presented on MHC II -> so the presentation ONLY goes through Macrophages which endocytosed the antigen and presented it later on a MHC II receptor to cd4 T cells? $\endgroup$ – Croin Aug 16 '17 at 20:51

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