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Something unknowable in immunology? Simple logic?

Dina Fonseca dfonseca at mail.sas.upenn.edu
Sun Jan 23 16:54:18 EST 1994

In article <2hsmer$4c5 at agate.berkeley.edu> frauwirt at mendel.Berkeley.EDU (Ken Frauwirth) writes:
>In article <2hs8sg$naa at netnews.upenn.edu>, dfonseca at mail.sas.upenn.edu 
>(Dina Fonseca) writes:
>|> To me, this begs the crucial question:
>|> Are there true peripheral antigens?
>|> I mean by this, are there proteins expressed and presented in the
>|> periphery, to which tolerance must be established by peripheral 
>|> mechanisms? For which failure of tolerance induction would lead to
>|> autoimmunity? Surely such self proteins must exist? 
>|> How could tolerance to such proteins possibly be established?
>Recent studies of autoimmune diseases suggest that this is exactly the
>case.  Tissue-specific proteins that are not secreted into the blood or
>lymph would have to induce tolerance peripherally (unless enough of the
>antigen is phagocytosed from dying cells or matrix).  Proteins such as 
>collagen (cartilage, bone - rheumatoid arthritis), TSH receptor (thyroid -
>Graves' disease), and acetylcholine receptor (neurons, muscles -
>myasthenia gravis) are all implicated in autoimmune diseases, and none
>should be available to developing T cells in the thymus (collagen might
>be available to developing B cells in bone marrow) for negative
>selection.  But just about any tissue-specific cellular or matrix protein
>would fit into the category of "peripheral antigens".  It has been
>suggested, however, that part of peripheral tolerance (perhaps a large
>part) is dependent on the fact that many of these proteins are probably
>not normally "visible" to the immune system in the absence of tissue
>damage, since they are not present in the blood or lymph.
>Ken Frauwirth                  BBB   IIIII    OO    K  K   EEEEE   N   N
>frauwirt at mendel.berkeley.edu   B  B    I     O  O   K K    E       NN  N
>Dept. of Molec. & Cell Bio.    BBB     I     O  O   KK     EEEE    N N N
>Immunology Division            B  B    I     O  O   K K    E       N  NN
>Univ. of Cal., Berkeley        BBB   IIIII    OO    K  K   EEEEE   N   N

I guess the point I'm trying to make is:
If there are true peripheral antigens in the sense I mean, then the
question of how the self-nonself decision is made in the periphery is a
truly difficult one. 

Just to recap: Peripheral antigens are expressed in the periphery, but not
at sufficient density continously in the thymus to induce tolerance in all
developing T cells throughout the lifetime of an individual. Moreover,
failure of tolerance induction to these antigens results in autoimmunity.
Finally, it is no answer to say that many proteins in the periphery are
not seen by the immune system, or are not expressed at sufficient density
on the appropriate APCs to trigger an immune response. These are the
proteins for which the lack of an immune response is EASY to explain. The
lack of an immune response does not constitute tolerance, as some have
I quote G. Morahan and JFAP Miller:

"It is important to note that such lack of activation [..such as occurs by
sequestration in an immunologically privileged site .....] is not
equivalent to tolerance induction since presentation of the antigen in an
immunogenic form would induce immunity. Tolerance is a state of specific
unresponsiveness induced by prior exposure to antigen."

It appears to me that one of two things is necessary to explain
unresponsiveness to self in the periphery: 

1) There are no peripheral antigens in the sense I have stated. This
involves one in many contradictions. One is that, given that minor
histoincompatible grafts are rejected, this assumption would necessitate
that no minor histoincompatability loci be true peripheral antigens.
However, there are many histoincompatability loci. Some of these are
known to be tissue specific. The fact that these can trigger an immune
response in a transplantation setting indicates that they are recognised
by T cells i.e. that they are expressed at sufficient density on the
appropriate APCs to trigger an immune response. Or if you believe that the
act of transplantation involves one in local inflammation that influences
the outcome of an immune response, let me state that they are also
recognized as immunogenic in a GVHD situation, where the only inflammation
is a size 27 needle applied i.v. 

2) The immune system can somehow distinguish true peripheral antigens from
non-self encountered in the periphery. 

But can anybody speculate (for I believe there is no hard data)- or if you
prefer the word, theorise, on how such a discrimination might possibly be
effected? I find the problem immensely stimulating. I do not believe the
answer is known, which gives this graduate student hope for real problems
remaining in Immunology. 

I should make it clear that I am using Dina Fonseca's account to follow
this discussion, having none of my own with access to newsgroups. And I am
still learning how to post accurately. 

Avinash Bhandoola.
Dept. of Immunology, U of Pennsylvania
avinash at reo.med.upenn.edu

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