The unveiling of hidden T-cell determinants of a native antigen by defined mediators of inflammation: implications for the pathogenesis of autoimmunity.
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.
Jiang
X
X
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
Moudgil
K D
KD
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D002403:Cathepsins / Q000737:chemistry; D016207:Cytokines / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000187:drug effects / Q000276:immunology*; D005260:Female; D016056:Immunodominant Epitopes / Q000032:analysis / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D009113:Muramidase / Q000737:chemistry / Q000276:immunology*
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; C421864:hen egg lysozyme; D009113:Muramidase; D002403:Cathepsins