Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.17 (lysozyme)
 21,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Efficient induction of self tolerance is critical for avoiding autoimmunity. The T cells specific for the well-processed and -presented (dominant) determinants of a native self protein are generally tolerized in the thymus, whereas those potentially directed against the inefficiently processed and presented (cryptic) self epitopes escape tolerance induction. We examined whether the crypticity of certain determinants of mouse lysozyme-M (ML-M) could be attributed to the nonavailability of a proteolytic site, and whether it could be reversed to immunodominance by engraftment of a novel cleavage site in the flanking region of the epitope. Using site-directed mutagenesis, we created the dibasic motif (RR or RK; R = arginine, K = lysine), a target of intracellular proteases, in the region adjoining one of the three cryptic epitopes (46-61, 66-79, or 105-119) of ML-M. Interestingly, the mutated lysozyme proteins, but not unmutated ML-M, were immunogenic in mice. The T cell response to the altered lysozyme was attributable to the efficient processing and presentation of the previously cryptic epitope, and this response was both epitope and MHC haplotype specific. In addition, the anti-self T cell response was associated with the generation of autoantibodies against self lysozyme. However, the results using one of three mutated lysozymes suggested that the naturally processed, dibasic motif-marked epitope may not always correspond precisely to the cryptic determinant within a synthetic peptide. This is the first report describing the circumvention of self tolerance owing to the targeted reversal of crypticity to dominance in vivo of a specific epitope within a native self Ag.
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PMID:Insertion of the dibasic motif in the flanking region of a cryptic self-determinant leads to activation of the epitope-specific T cells. 1608 93

A major hypothesis for the induction of autoimmunity invokes the enhanced display of previously hidden (cryptic) epitopes under inflammatory conditions leading to the activation of self-reactive T cells. However, there is meager data that directly validate the influence of specific immune mediators on the upregulation of the presentation of cryptic determinants in vivo. We tested the effect on well-defined cryptic epitopes of hen eggwhite lysozyme (HEL) of the availability locally of a cytokine (IL-2, IL-4, IL-6, IL-10, TNF-alpha or granulocyte-macrophage colony-stimulating factor) at the antigen delivery site, or of the pretreatment of the immunogen with a cathepsin (Cat B, D, L or S) prior to use in vivo. Each of the three mouse strains (H-2(b/d/k)) tested revealed a unique profile of T-cell reactivity to different cryptic epitopes of HEL in response to a particular cytokine or cathepsin. These results provide proof of principle for the reversal of crypticity of self-epitopes by immune mediators in the local milieu. Moreover, co-immunization with an antigen and a cytokine offers a simple and reliable tool for studying the role of cryptic epitopes in autoimmunity. Our results also strengthen the rationale for the use of inhibitors of cytokine/cathepsin activity in the treatment of autoimmune diseases.
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PMID:The unveiling of hidden T-cell determinants of a native antigen by defined mediators of inflammation: implications for the pathogenesis of autoimmunity. 1664 Jun 57

The immune system of a healthy individual responds vigorously to foreign microbial antigens. However, all potentially immunogenic regions (determinants) within an antigen are not functionally of equal relevance in mediating host immunity against the pathogen. Moreover, some of these antigenic determinants are well processed and presented (immunodominant), while others are not revealed (cryptic) from the native antigen. Nevertheless, cryptic determinants are good immunogens in the pre-processed peptide form. Defining the factors influencing the dominance versus the crypticity of antigenic determinants is critical to advancing our understanding of the individual variations in host immunity to infection, autoantigens and vaccination. In this study based on a model antigen, hen eggwhite lysozyme (HEL), we describe that the major histocompatibility complex (MHC) haplotypes imprint and the non-MHC genes modify the dominance versus the crypticity of a specific antigenic determinant. Both the H-2(q)- and the H-2(d)-bearing mice raised potent response to native HEL, but responded differently to its determinant region 57-78, which was dominant in the H-2(q) but cryptic in the H-2(d) mice. The H-2(q)- but not the H-2(d)-bearing mice of three different genetic backgrounds yielded patterns of graded reactivity to epitope 57-78 showing the fine-tuning effect of the non-MHC genes. Interestingly, the F1 (H-2(q) x H-2(d)) mice retained the dominant response profile of the H-2(q) parent regardless of the contributing gender, and also responded to a new sub-determinant 61-75. These results highlight the genetic factors influencing the dominance/crypticity of a specific antigenic determinant.
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PMID:The major histocompatibility complex haplotypes dictate and the background genes fine-tune the dominant versus the cryptic response profile of a T-cell determinant within a native antigen: relevance to disease susceptibility and vaccination. 1725 20