The Unveiling of Hidden T‐Cell Determinants of a Native Antigen by Defined Mediators of Inflammation: Implications for the Pathogenesis of Autoimmunity

Abstract

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.

Additive Effect of Preservative-free Sodium Hyaluronate 0.1% in Treatment of Dry Eye Syndrome With Diquafosol 3% Eye Drops

“…23 Benzalkonium chloride, contained in diquafosol, is known to be degraded into hydrogen peroxide (H 2 O 2 ), 24 and can cause oxidative damage to corneal and conjunctival epithelial cells even in small amounts, as low as 0.003%. 25 It also has the potential to initiate ocular surface damage and subconjunctival inflammation.…”

Recognition of HIV-1 Peptides by Host CTL Is Related to HIV-1 Similarity to Human Proteins

“…It was proposed that self-tolerance might be infringed in autoimmunity by the activation of T cells directed against cryptic self-determinants [15], [16]: well-processed and -presented antigenic determinants are immunodominant, while poorly processed/presented ones curtail the activation of specific T cells and are thus cryptic. Then, certain conditions (e.g., addition of a cleavage site [17] or of inflammatory mediators [18]) can help circumvent self tolerance and thereby lead to autoimmunity. Viral or bacterial infections have also been suspected as triggering factors for autoimmune disorders, possibly through molecular mimicry and/or bystander activation of autoreactive cells.…”

Evaluation of Biomarkers of Inflammation in Response to Benzalkonium Chloride on Corneal and Conjunctival Epithelial Cells

“…13,14 In fact, tear samples from glaucoma patients have been shown to have greater amounts of infl ammatory cytokines compared to their normal counterparts. 49 Although fi brinogen is suspected as being upregulated indirectly (secondary to the infl ammatory cytokines), 50 it (ie, fi brinogen), 12 CRP, 11 and multiple cytokines, 13,14 specifi cally IL-1α and β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-23, and TNFα, have long been described as conventional markers of infl ammation. used in concentrations varying from 0.015% to 0.05%, 4 although the American College of Toxicology has concluded that BAK can be safely used as an antimicrobial agent at concentrations up to 0.1%.…”

“…8 BAK, is known to be degraded into hydrogen peroxide (H 2 O 2 ), 8 which, in even small amounts as low as 30 parts per million (0.003%), is known to be an ophthalmic irritant. 9,10 C-reactive protein (CRP), 11 fi brinogen, 12 and multiple cytokines, 13,14 specifi cally interleukin (IL-)1α and β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-23, and tumor necrosis factor (TNF-)α, have long been described as conventional biomarkers of infl ammation. Increased toxicity should cause a localized infl ammatory response with concomitant increased elaboration of these infl ammatory biomarkers.…”