can you publish

David Usharauli davidusharauli at nilc.org.ge
Thu Apr 26 05:04:10 EST 2001

     Let me introduce myself to you. My name is David usharauli. I am fifth year student. I study at the Tbilisi state medical University, Georgia. I am intersted in theoretical field of Immunology. I have an original hypothesis about possible mechanism OF PERIPHERIAL TOLERANCE. I want introduce it to you. 
    The novel mechanism of peripheral tolerance 
    David Usharauli 


    I present here a novel model of peripheral tolerance mediated by a anatomical difference between the distribution of antigen presenting cells(APC) for tolerance and for activation in the peripheral lymphoid tissues.The new model includes also another important conclusion:there is local,rather universal,diffuse tolerance to self. 


    T cells that recognize self antigens are commonly eliminated in the Thymus. Such clonal deletion represents an important protection from autoimmune desease,but it’s effects are limited to proteins that are expressed within the thymus and can be presented to developing T cells,largerly by thymus dendritic cells(DCs) or macrophages .Hence,it is not surprizing that many autoantigens are proteins with limited distribution,for which this mechanism of central tolerance can’t be used.That in most cases there is no responses to such proteins suggests that some other mechanism or mechanisms must prevent T cells responses to such antigens. But all these mechanisms fail to explain how is made dicision between self and nonself reactive T cells by the antigen presenting-cells(APC),because the APC itself can not favor activation of nonself reactive T cells and inactivation of self reactive T cells.That why any peripheral tolerance models must include the screening mechanism for both types of T cells, which favor interaction of nonself reactive T cells with the mature DCs and doesn’t the same with the self reactive T cells. Taking into account the recent publication about DCs fuction and their distribution, I have hypothetized that the anatomical difference between the distribution of the immature(resting) and mature(activated) DCs in the peripheral lymphoid tissues may contribute to this mechanism. 

    hypothesis of "tolerance gate" 

    Cell death can be achieved in a variety of ways,popularly classified into two:apoptotic and necrotic.Cells undergoing programmed cell death[apoptosis] are repeadly ingested by the phagocytic cells,mostly by immature,resting DCs in their vicinity.The ingested cell is then completely broken down and digested by the immature DCs without the induction of costimulatory,thus apoptosis is normally an immunologically "quiet" process,that is apoptotic cell do not normally contribute to or stimulate immune responses. In addition, recognition and engulfement of apoptotic cells by professional antigen presenting cells, such as dendritic cells, and their interaction with effector immune cells have been recently described to result in apoptotic cell-derived antigen specific tolerance. Cell death by necrosis is typically associated with inflammation, in contrast to apoptosis,recently it was demonstrated difference between the two types of death that occur at the level of DCs ,where necrotic but not apoptotic cells mediated maturation,activation of immature/resting DCs.The immature DCs after ingestion of apoptotic cells,express epitopes of apoptotic particles with MHC class I and II ,but they fail costimulatory molecules such as B7,that why the immature DCs can tolerize self reactive T cells,because the apoptotic particles contain only "self" epitopes. In contrast to immature DCs , the mature DCs have costimulatory capacity and can activate as self as nonself reactive T cells. That’s why, it is important for organism to keep the mature DCs afar from self reactive T cells. How can be achieved it? 

    The different localization of the immature/mature DCs in the peripheral lymphoid tissues can secure it. 

    The priming of naive T cells occurs in the peripheral lymphoid organs e.g. lymph nodes(16),where after activation and maturation migrate DCs. T cells recyrculate via HEV(high endothelial venules) the lymph nodes(LNs) ,But the cyrculating pool of lymphocytes contains as self as nonself reactive T cells.I hypothetized, that T cells to reach mature DCs must pass through the leyer of immature DCs,which constitutively phagocytose and transport apoptotic cells to the near lymph nodes and express only "self" epitopes.Thus ,any self reactive T cells will be trapped by the immate DCs leyer and will delete or become anergic after interaction with the laters.The leyer of immature DCs is will be crossed only by those T clones which are not self reactive and can reach the site where mature DCs are localized. 

    So, such distribution of the immature/mature DCs in the peripheral the lymphoid organs secures the elimination of all autoreactive T clones. 

    Possible mechanism of different location of the immature/mature DCs in the peripheral the lymphoid organs. 

    The different subclass of DCs may express "homing receptors," similar to those of T cells, for certain endothelia. It must be at least two sites of resedence for DCs in the peripheral lymphoid organs: First,I coin it TOLERANCE SITE contains the complex of adhesive molecules , which are complementary to the receptors of the immature DCs, so migration of the immature DCs through the peripheral lymphoid organs is arrested in the environment of those adhesive molecules, and in such case the leyer is built TOLERANCE SITE , so all T cells interact with the immature DCs firstly, passing through the peripheral lymphoid organs. Second site,I coin it PRIMING SITE contains the different complex of adhesive molecules. These molecules are complementary to the receptors of the mature DCs. It means that upon activation, DCs change their adhesive molecules profile, they acquire the new complex of adhesive molecules, so they are not arrested by the tolerance site and thus the mature DCs can cross it and enter the priming site where they are arrested and build the T clones PRIMING SITE. 

    Thus all the self reactive T clones are anergized in the site of tolerance. Only the nonself reactive T clones can cross the tolerance site and enter the priming site. 

    The main principle is that the leyer of mature DCs are localized behind the leyer of immature DCs in the peripheral lymphoid organs. 

    Such as nonspecific mechanism secures absolutely specific negative/positive selection of T clones in the peripheral lymphoid organs. 

    from this hypothesis issues one important conclusion: there is local rather universal,diffuse tolerance to self.Tissue and organ specific antigens are antigens with limited distributoin.The cells of such tissues constitutively udergo apoptosis and are phagocytose by the immature DCs in their vicinity and transported to near lymph nodes,where immature DCs tolerize T cells specific for antigens of apoptotic cells.It means that each lymph node tolerize only those self reactive T cells specific for epitopes charactable for tissues draining by the lymph node.That is,the immature DCs of skin-associated lymph nodes tolerize only those self reactice T cells,which are specific for antigens associated with the skin and do not tolerize T cells specific for antigens from e.g. CNS or gaster. It can only those LNs, which are to the near from CNS or gaster. Therefore, if we inject the myelin basic protein(MBP)+adjuvants in the skin,always occurs autoclons activation specific for MBP,then they migrate to CNS and only after some time they will anergize by LNs,which contain the leyer of immature DCs expessing epitopes of CNS.Thus we have always transient autouimmune deasese after injection of MBP+adjuvants in the skin(28,29).But if we inject the same antigen directly in the CNS or near to it,no autoimmune deasese develop.it means that tolerance is tissue specific i.e. when we inject e.g. gastric antigens+adjuvant in the skin, it occur transient autoimmune gastritis till all autoreactive T clons will be eliminated by the LNs associeted with gaster.But if we inject the same antigens directly in the gastric tissue no autoimmune deases develop. Because in normal condition the tissue specific epitopes of apoptotic partircles are ingested by the immature DCs of local LN, no dislocation of tissue specific epitopes from one to another specific tissue occur,and thus, although in norm we have gastric specific autoclons in the lymph nodes of skin,no autoclons can be activated,because there are no gastric specific epitpos in the LNs of skin. 

    Such as explanation can help us to understand why develop autoimmune deseases after some infection.If e.g. streptococus has epitopes,which are similar to self epitopes e.g. kidney(30,31) and this epitopes are not in the tissue,where infection has developed(Tonsills)self reactive autoclons can activate and cause pesistance of autoimmune deasese during the chronical infection.that why only eridication of streptococus can stop this deaseses. 

    Although,there are many experimental evidences for this hypothesis,which support it indirectly,it is needed futher investigation to get evidences,which can support it directly. 

    please write me only via next E-mail : davidusharauli at hotmail.com

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