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MHC-II proteins are presenting antigens on the surface of cells with lysosomal activities where they eventually might get transported off by some T-cell receptor-anti-gens, as far as I understand (pls apologise and correct me if I am wrong). I would be interested in two questions regarding this specific immuno-cascade reaction.

  1. It appears that in cases self-pepties are bound to the MHC-II proteins (say HLA-DP2) when they are at the surface already. Where do such self-peptides come from? Do they come from inside the endosomal active cell or could they also come from "outside" from where the T-cell comes?

  2. What would happen if (for some reason) a) the self-peptide binds "irreversibly" to the MHC-II? b) the self peptide binds irreversibly to the MHC-II and at the same time is structurally significantly distorted (e.g. if there is something, like a heavy metal bound in-between the MHC-II and the self-peptide)?

(I apologise for the case I got some terminology wrong or some basic concepts, I am no specialist in bio-chemistry.)

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It appears that in cases self-pepties are bound to the MHC-II proteins (say HLA-DP2) when they are at the surface already. Where do such self-peptides come from?

Class II MHC molecules are capable of presenting any peptide of appropriate length, regardless of where it came from. Contents in a phagolysosome will contain both self and non-self peptides.

Do they come from inside the endosomal active cell

Some do, yes. While many proteins are degraded by the proteosome, some are actively imported into a lysosome and degraded there. This is termed chaperone-mediated autophagy. Full organelles may also be brought into the lysosome through "regular" autophagy.

or could they also come from "outside" from where the T-cell comes?

This is the case as well. Any ingested material from the outside could contain cellular debris, protein agglutinations, or foreign organisms. Peptides from all of these sources can be presented at the cell surface.

What would happen if (for some reason) a) the self-peptide binds "irreversibly" to the MHC-II?

According to this study, MHC II molecules are recycled, and their turnover is carefully regulated. There is no need for the bound peptide to dissociate during antigen presentation, so likely problems would occur when MHC II turnover is disrupted.

the self peptide binds irreversibly to the MHC-II and at the same time is structurally significantly distorted (e.g. if there is something, like a heavy metal bound in-between the MHC-II and the self-peptide)?

If the MHC itself is structurally distorted, it will not be recognized by any other cells. Remember that, during T cell selection, the cells must be able to recognize the MHC itself with a low affinity. T cells which bind strongly to the MHC itself undergo death by negative selection, whereas those which do not recognize the MHC at all undergo death by neglect. As a significant structural change would result in either an excessive affinity, or no affinity, no T cells capable of recognizing the complex would be present.

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  • $\begingroup$ Thank you very much, that answers all but the last part. What I meant was what would happen if the self-peptide is distorted by the complexation. As far as I understand, there is (must be) some regulation against developing an immuno-response against self-peptides. But the question would be what would most likely happen if the self peptide is so strongly distorted, that it is no longer recognisable as a self-peptide. Does this make sense? In case what would happen? $\endgroup$ – Rudi_Birnbaum Nov 18 '17 at 10:22
  • $\begingroup$ "Class II MHC molecules are capable of presenting any peptide of appropriate length" Just to clarify this, MHC molecules are not capable of presenting any peptide, but rather present a subset of peptides that have the required sequence determinants that allow binding in the MHC groove. Often there are key 'anchor' residues in the peptide that bind to hydrophobic pockets on the floor of the MHC binding groove. You are right in saying that it doesn't matter where the peptide came from though. $\endgroup$ – Andrew Guy Jan 7 '18 at 2:47

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